Substituted indoles

ABSTRACT

Substituted indoles of the formula (I) and physiologically acceptable derivatives and salts thereof, in which R 1 , D, E, R 12 , p, X 1 , E, G, X 2  and Z are as defined in claim  1 , exhibit particular actions on the central nervous system, especially 5HT reuptake-inhibiting and 5 HTx-agonistic and/or -antagonistic actions and in particular serotonin-agonistic and -antagonistic properties and can be employed as antipsychotics, neuroleptics, antidepressants, anxiolyties and/or antihypertonics. They can furthermore be employed as excitatory amino acid antagonists for combating neurodegenerative diseases, including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, cerebral ischaemia, infarction or psychoses

The invention relates to substituted indoles of the formula I

in which

-   -   R¹ is H, A or SO₂A,    -   A is straight-chain or branched alkyl having from 1 to 10 carbon        atoms, alkenyl having from 2 to 10 carbon atoms or alkoxyalkyl        having from 2 to 10 carbon atoms, and    -   D-E is R²C═CR⁴ or R²R³C—CR⁴R⁵,        -   in which        -   R², R³, R⁴ and R⁵ are selected, independently, from H, A,            cycloalkyl having from 3 to 7 carbon atoms, Hal, CH₂Hal,            CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)N(R⁶)₂,            (CH₂)_(n)N(R⁶)Ar, (CH₂)_(n)N(R⁶)Het, (CH₂)_(n)N(Ar)₂,            (CH₂)_(n)N(Het)₂, (CH₂)_(n)COOR⁶, (CH₂)_(n)COOAr,            (CH₂)_(n)COOHet, (CH₂)_(n)CON(R⁶)₂, (CH₂)_(n)CON(R⁶)Ar,            (CH₂)_(n)CON(R⁶)Het, (CH₂)_(n)CON(Ar)₂, (CH₂)_(n)CON(Het)₂,            (CH₂)_(n)NR⁶COR⁶, (CH₂)_(n)NR⁶CON(R⁶)₂, (CH₂)_(n)NR⁶SO₂A,            (CH₂)_(n)SO₂N(R⁶)₂, (CH₂)_(n)SO₂NR⁶(CH₂)_(m)Ar,            (CH₂)_(n)SO₂NR⁶(CH₂)_(m)Het, (CH₂)_(n)S(O)_(w)R⁶,            (CH₂)_(n)S(O)_(w)Ar, (CH₂)_(n)S(O)_(w)Het, (CH₂)_(n)OOCR⁶,            (CH₂)_(n)Het, (CH₂)_(n)Ar, (CH₂)_(n)COR⁶,            (CH₂)_(n)CO(CH₂)_(m)Ar, (CH₂)_(n)CO(CH₂)_(m)Het,            (CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het,            (CH₂)_(n)OR⁶, (CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het,            (CH₂)_(n)SR⁶, (CH₂)_(n)S(CH₂)_(m)Ar, (CH₂)_(n)S(CH₂)_(m)Het,            (CH₂)_(n)N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)(CH₂)_(m)Het,            (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar,            (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het,            (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Ar,            (CH₂)_(n)N(R⁶)CO(CH₂)_(m)Ar, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Het,            (CH₂)_(n)N(R⁶)CO(CH₂)_(m)Het, CH═N—OA, CH₂CH═N—OA,            (CH₂)_(n)NHOA, (CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR⁶,            (CH₂)_(n)OC(O)N(R⁸)₂, (CH₂)OC(O)NR⁶(CH₂)_(m)Ar,            (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het, (CH₂)_(n)NR⁶COOR⁶,            (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar, (CH₂)_(n)NR⁶COO(CH₂)_(m)Het,            (CH₂)_(n)N(R⁶)CH₂CH₂OR⁶, (CH₂)_(n)N(R⁶)CH₂CH₂OCF₃,            (CH₂)_(n)N(R⁶)C(R⁶)HCOOR⁶, (CH₂)_(n)N(R⁶)CH₂COHet,            (CH₂)_(n)N(R⁶)CH₂Het, (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)CH₂COOR⁶,            (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)₂, CH═CHCOOR⁶, CH═CHCH₂NR⁶Het,            CH═CHCH₂N(R⁶)₂, CH═CHCH₂OR⁶, (CH₂)_(n)N(COOR⁶)COOR⁶,            (CH₂)_(n)N(CONH₂)COOR⁶, (CH₂)_(n)N(CONH₂)CONH₂,            (CH₂)_(n)N(CH₂COOR⁶)COOR⁶, (CH₂)_(n)N(CH₂CONH₂)COOR⁶,            (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR⁶COR⁶,            (CH₂)_(n)CHR⁶COOR⁶, (CH₂)_(n)CHR⁶CH₂OR⁶, (CH₂)_(n)OCN or            (CH₂)_(n)NCO, in which    -   R⁶ is selected, independently, from H, A or cycloalkyl having        from 3 to 7 carbon atoms,    -   Het is a saturated, unsaturated or aromatic mono- or bicyclic        heterocyclic radical which is unsubstituted or mono- or        poly-substituted by A, Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶,        CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂N(R⁶)₂,        S(O)_(w)A and/or OOCR⁶,    -   Ar is an aromatic hydrocarbon radical having from 6 to 14 carbon        atoms which is unsubstituted or mono- or polysubstituted by A,        Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂, NR⁶COR⁶,        NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶,    -   w is 0, 1, 2 or 3, and    -   n and m, independently of one another, are 0, 1, 2, 3, 4 or 5;    -   X¹ is (CHR⁷)_(g) or (CHR⁷)_(h)-Q-(CHR⁸)_(k), in which    -   Q is selected from O, S, N—R⁶, (O—CHR⁷)_(g), (CHR⁷—O)_(g),        CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g), (CHR⁹CHR¹⁰—O)_(g), C═O, C═S, C═NR⁶,        CH(OR⁶), C(OR⁶)(OR⁶), C(═O)O, OC(═O), OC(═O)O, C(═O)N(R⁶),        N(R⁶)C(═O), C(═S)N(R⁶), N(R⁶)C(═S), OC(═O)N(R⁶), N(R⁶)C(═O)O,        CH═N—O, CH═N—NR⁶, OC(O)NR⁶, NR⁶C(O)O, S═O, SO₂ SO₂NR⁶ and        NR⁶SO₂,    -   g is 1, 2, 3, 4, 5 or 6,    -   h and k, independently of one another, are 0, 1, 2, 3, 4, 5 or        6, and    -   R⁷, R⁸, R⁹, R¹⁰ and R¹² are selected, independently, from the        meanings indicated for R² to R⁵;    -   p is 0, 1, 2 or 3    -   E is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar or cycloalkyl having from 3        to 7 carbon atoms,    -   G is an optionally substituted alkylene radical having from 1 to        4 carbon atoms, where the substituents are selected from the        meanings indicated for R⁴,    -   or    -   E and    -   G, together with the N atom to which they are bonded, are an        unsubstituted or substituted 5-, 6- or 7-membered, mono- or        bicyclic heterocyclic radical, which may have 1, 2 or 3 further        heteroatoms selected from N, O and S,    -   X² is a bond or is selected, independently, from the meanings        indicated for X¹,

Z is H or is a saturated, mono- or polyethylenically unsaturated oraromatic carbocyclic radical having from 5 to 10 carbon atoms or asaturated, mono- or polyethylenically unsaturated or aromaticheterocyclic radical having from 4 to 9 carbon atoms, where thecarbocyclic or heterocyclic radical may be mono- or polysubstituted,where the substituents are selected, independently of one another, fromthe meanings of R² to R⁵ other than H, and where the heterocyclicradical contains from 1 to 4 heteroatoms selected, independently of oneanother, from N, O and S,

-   -   and    -   Hal is F, Cl, Br or I,        and salts and solvates thereof, preferably physiologically        tolerated salts and solvates thereof and in particular        physiologically tolerated salts thereof.

Benzylpiperidine derivatives with high affinity to binding sites ofamino acid receptors are disclosed, for example, in EP 0 709 384 A1.

The invention had the object of finding novel compounds having valuableproperties, in particular those which have an improved action profile,for example higher activity, higher selectivity or a broader use profileand/or less severe side effects. It should preferably be possible toprepare the novel compounds simply and inexpensively, and they shouldbe, in particular, suitable for the preparation of medicaments.

Surprisingly, it has been found that the object is achieved by thecompounds of the formula I. In particular, it has been found that thecompounds of the formula I and salts thereof have very valuablepharmacological properties as well as being well tolerated.

The compounds according to the invention exhibit particular actions onthe central nervous system, especially SHT reuptake-inhibiting and5HT_(x)-agonistic and/or -antagonistic actions, where HT_(x) ispreferably taken to mean HT_(1A), HT_(1D), HT_(2A) and/or HT_(2C).

Since the compounds inhibit serotonin reuptake, they are particularlysuitable as antipsychotics, neuroleptics, antidepressants, anxiolyticsand/or antihypertonics. The compounds exhibit serotonin-agonistic and-antagonistic properties. They inhibit the binding of tritiatedserotonin ligands to hippocampal receptors (Cossery et al., European J.Pharmacol. 140 (1987), 143-155) and synaptosomal serotonin reuptake(Sherman et al., Life Sci. 23 (1978), 1863-1870). In addition, changesin DOPA accumulation in the striatum and 5-HT accumulation in variousregions of the brain occur (Seyfried et al., European J. Pharmacol. 160(1989), 31-41). The 5-HT_(1A)-antagonistic action is detected in vitro,for example, by inhibition of the abolition of electrically inducedcontraction of the guinea pig ileum caused by 8-OH-DPAT (Fozard andKilbinger, Br. J. Pharmacol. 86 (1985) 601P). The 5-HT_(1A)-antagonisticaction is detected ex vivo by inhibition of 5-HTP accumulation reducedby 8-OH-DPAT (Seyfried et al., European J. Pharmacol. 160 (1989), 31-41)and the antagonisation of 8-OH-DPAT-induced effects in the ultrasoundvocalisation test (DeVry, Psychpharmacol. 121 (1995), 1-26). Inhibitionof serotonin reuptake can be detected ex vivo using synaptosomal uptakeinhibition (Wong et al., Neuropsychopharmacol. 8 (1993), 23-33) andp-chloroamphetamine antagonism (Fuller et al., J. Pharmacol. Exp. Ther.212 (1980), 115-119). Furthermore, analgesic and hypotensive actionsoccur.

The compounds are therefore suitable for the treatment of schizophrenia,cognitive deficits, anxiety, depression, nausea, tardive dyskinesia,gastrointestinal tract disorders, learning disorders, age-related memorydisorders, psychoses and for positively influencing obsessive-compulsivedisorder (OCD) and eating disorders (for example bulimia). They exhibitactions on the central nervous system, in particular additional5-HT_(1A)-agonistic and 5-HT reuptake-inhibiting actions. They arelikewise suitable for the prophylaxis of and combating the consequencesof cerebral infarction (apoplexia cerebri), such as strokes and cerebralischaemia, and for the treatment of extrapyramidal motor side effects ofneuroleptics and of Parkinson's disease.

The compounds of the formula I are therefore suitable both in veterinaryand in human medicine for the treatment of dysfunctions of the centralnervous system and of inflammation. They can be used for the prophylaxisof and for combating the consequences of cerebral infarction (apoplexiacerebri), such as strokes and cerebral ischaemia, and for the treatmentof extrapyramidal motor side effects of neuroleptics and of Parkinson'sdisease, for the acute and symptomatic therapy of Alzheimer's diseaseand for the treatment of amyotrophic lateral sclerosis. They arelikewise suitable as therapeutic agents for the treatment of brain andspinal cord trauma. However, they are also suitable as medicament activeingredients for anxiolytics, antidepressants, antipsychotics,neuroleptics, antihypertonics and/or for positively influencingobsessive-compulsive disorder, sleeping disorders, tardive dyskinesia,learning disorders, age-related memory disorders, eating disorders, suchas bulimia, and/or sexual dysfunctions.

The compounds according to the invention particularly preferably exhibithigh bioavailability and/or are capable of significantly increasing theserotonin level in the brain.

The present invention therefore relates to compounds according to theinvention as medicament or medicament active ingredient.

The present invention therefore relates to the use of the compoundsaccording to the invention for the preparation of a medicament for theprophylaxis and/or therapy of diseases in which 5HT plays a role.

These diseases are preferably selected from depression, strokes,cerebral ischaemia, extrapyramidal motor side effects of neurolepticsand of Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis, brain and spinal cord trauma, obsessive-compulsive disorder,sleeping disorders, tardive dyskinesia, learning disorders, age-relatedmemory disorders, eating disorders, such as bulimia, and/or sexualdysfunctions.

Furthermore, the compounds according to the invention preferably exhibitparticularly high affinity to binding sites of amino acid receptors, inparticular to the ifenprodil binding site on the NMDA receptor(NMDA=N-methyl D-aspartate), which allosterically modulates thepolyamine binding site.

The binding test for [³H]-ifenprodil can be carried out by the method ofSchoemaker et al., Eur J. Pharmacol. 176, 249-250 (1990).

The compounds are suitable for the treatment of neurodegenerativediseases, including cerebrovascular diseases. The novel compounds canlikewise be used as analgesics or anxiolytic and for the treatment ofepilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease,Huntington's disease, cerebral ischaemia or infarction. They arefurthermore suitable for the treatment of psychoses caused byexcessively high amino acid levels.

The [³H]-CGP-39653 binding test for the glutamate binding site of theNMDA receptor can be carried out, for example, by the method of M. A.Stills et al., described in Eur. J. Pharmacol. 192, 19-24 (1991). Thetest for the glycine binding site of the NMDA receptor can be carriedout by the method of M. B. Baron et al., described in Eur. J. Pharmacol.206, 149-154 (1991).

The action against Parkinson's disease, i.e. potentiation of theL-DOPA-induced contralateral rotation in hemiparkinsonian rats, can bedemonstrated by the method of U. Ungerstedt and G. W. Arbuthnott, BrainRes. 24, 485 (1970).

The compound is particularly suitable for the treatment or prophylaxisof strokes and for protection against and for the treatment of cerebraloedema and states of undersupply of the central nervous system, inparticular hypoxia or anoxia.

The said effects can in addition be demonstrated or checked by themethods as described in the following references.

-   J. W. McDonald, F. S. Silverstein and M. V. Johnston, Eur. J.    Pharmacol. 140, 359 (1987); R. Gill, A. C. Foster and G. N.    Woodruff, J. Neurosci. 7, 3343 (1987); J. B. Bederson et al.,    Stroke, 17 472-476 (1986); S. Brint et al., J. Cereb. Blood Flow    Metab. 8, 474-485 (1988).

The references listed below disclose various antagonists which are ableto block various binding sites of the NMDA receptor:

-   W. Danysz, C. G. Parsons, t. Bresink and G. Quack, Drug, News &    Perspectives 8, 261 (1995), K. R. Gee, Exp. Opin. Invest. Drugs 3,    1021 (1994) and J. J. Kulagowski and L. L. Iversen, J. Med. Chem. 37    4053 (1994).

Ifenprodil and eliprodit of the formulae IV and V respectively are ableto block the NMDA receptor by interacting with the modulatory polyaminebinding site (C. J. Carter, K. G. Lloyd, B. Zivkovic and B. Scatton, J.Pharmacol. Exp. Ther. 253, 475 (1990)).

Since ifenprodil and eliprodit interact with the polyamine binding siteon the NMDA receptor, the antagonistic activity of the compoundsaccording to the invention can be determined in a spermine-stimulated[³H]MK-801 (dizocilpine) binding test.

In the presence of saturation concentrations of glycine and NMDA,spermine is able further to increase the binding of MK-801, which isinhibited by ifenprodil, eliprodil and very particularly effectively bythe compounds according to the invention.

In addition, the compounds according to the invention can be tested in a[³H]GABA (γ-aminobutyric acid) liberation test, analogously to J.Dreijer, T. Honoré and A. Schousboe, J. Neurosci. 7, 2910 (1987), which,as an in-vitro model, describes the antagonistic function in the cell.

The invention accordingly relates to the compounds of the formula Iaccording to claim l and/or physiologically acceptable salts thereof asantagonists to receptors of excitatory amino acids, such as, forexample, glutamic acid, and salts thereof.

The invention relates to the compounds of the formula I according toclaim 1 and physiologically acceptable salts and solvates thereof asglycine transporter inhibitor.

In particular, the invention relates to the compounds of the formula Iaccording to claim 1 and/or acceptable salts thereof as excitatory aminoacid antagonists for combating neurodegenerative diseases, includingcerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease,Parkinson's disease, Huntington's disease, cerebral ischaemia,infarction or psychoses.

The invention also relates to the use of the compounds of the formula Iaccording to claim 1 and/or physiologically acceptable salts thereof forthe preparation of a medicament for combating neurodegenerativediseases, including cerebrovascular diseases, epilepsy, schizophrenia,Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebralischaemia, infarction or psychoses.

The compounds of the formula I can be employed as medicament activeingredient in human and veterinary medicine.

The invention furthermore relates to a process for the preparation ofthe compounds of the formula I according to claim 1 and physiologicallyacceptable salts thereof, characterised in that

-   -   a) a compound of the formula II

-   -   in which    -   L¹ is Cl, Br, I, OH, a reactively esterified OH group or a        diazonium group, and R¹, D, E, R¹², p and X¹ are as defined        above and below for the compounds of the formula I,    -   b) is reacted with a compound of the formula III

-   -   -   in which        -   L² is H or a metal ion, and E, G, X² and Z are as defined            above and below for the compounds of the formula I,        -   and optionally

    -   d) the resultant compound of the formula I is converted into one        of its salts by treatment with an acid.

In a preferred embodiment, the compound of the formula III is selectedfrom compounds of the formula

in which L², q, Y, X² and Z are as defined above and below.

The compound of the formula VI is particularly preferably selected fromcompounds of the formulae

or the thioamides thereof,in which L², X² and Z are as defined above and below, and R′ is H, A,(CH₂)_(n)Het, (CH₂)_(n)Ar, cycloalkyl having from 3 to 7 carbon atoms orSO₂A.

The process according to the invention can be carried out as a one-potreaction, i.e. isolation and/or purification steps are omitted as far aspossible and only the desired end product, i.e. generally a compoundaccording to the invention or a pharmaceutically usable derivativethereof, is purified and/or isolated. Alternatively, a purificationand/or isolation step can be carried out after each of the said reactionsteps. Mixed forms of the procedures described above are alsoconceivable. Suitable purification and isolation steps are known to theperson skilled in the art, for example from Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Stuttgart.

In particular, the invention relates to the compounds of the formula Iin which at least one of the said radicals has one of the preferredmeanings indicated above.

For the purposes of the present invention, alkyl is a linear or branchedalkyl radical, preferably an unbranched alkyl radical, which has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5carbon atoms, and may be mono- or polysubstituted by halogen (Hal), forexample perfluorinated. If an alkyl radical is substituted by halogen,it preferably, depending on the number of carbon atoms of the alkylradical, has 1, 2, 3, 4 or 5 halogen atoms. Thus, for example, a methylgroup (alkyl radical having 1 carbon atom) can be mono-, di- ortrisubstituted by halogen, and an ethyl group (alkyl radical having 2carbon atoms) can be mono-, di-, tri-, tetra- or pentasubstituted byhalogen.

For alkyl groups having more than 2 carbon atoms, the same preferablyapplies as for ethyl groups. Alkyl is particularly preferably methyl,ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermorepreferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but alson-pentyl, neopentyl, isopentyl or hexyl.

The term “alkenyl” preferably covers mono- or polyethylenicallyunsaturated, straight-chain or branched hydrocarbon radicals having from2 to 10 and in particular from 3 to 6 carbon atoms, and in particularallyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, furthermore preferably4-pentenyl, isopentenyl or 5-hexenyl.

The term “alkoxy” is preferably a radical of the formula —O-alkyl, inwhich alkyl is as defined above, or, if two alkoxy radicals are bondedto adjacent (vicinal) carbon atoms, “alkoxy” is preferably—O-alkylene-O—, in which alkylene is as defined above. Preferred alkoxyradicals of the formula —O-alkyl are methoxy, ethoxy and propoxy.Preferred alkoxy radicals of the formula —O-alkylene-O— are —O—CH₂—O—,—O—CH₂CH₂—O— and —O—CH₂CH₂CH₂—O—.

The term “alkoxyalkyl” preferably covers straight-chain radicals of theformula C_(u)H_(2u+1)—O—(CH₂)_(v), in which u and v are each,independently of one another, from 1 to 6. Particularly preferably, u=1and v=1 to 4.

The term “aryl” preferably covers an unsubstituted or mono- orpolysubstituted benzene ring, for example an unsubstituted orsubstituted phenyl radical or an unsubstituted or mono- orpolysubstituted system of benzene rings, such as, for example,anthracene, phenanthrene or naphthalene ring systems. Examples ofsuitable substituents include alkyl, alkoxy, oxo, hydroxyl, mercapto,amino, nitro, cyano and halogen radicals.

The term “aryl” preferably covers an unsubstituted or mono- orpolysubstituted aromatic ring system, for example an unsubstituted orsubstituted phenyl radical or an unsubstituted or mono- orpolysubstituted system of benzene rings, such as, for example,anthracene, phenanthrene or naphthalene ring systems. Examples ofsuitable substituents include alkyl, alkoxy, oxo, hydroxyl, mercapto,amino, nitro, cyano and halogen radicals.

The term “aralkyl” preferably covers an aryl radical as defined abovebonded to an alkyl radical as defined above. Examples of suitablearalkyl radicals include, but are not restricted to, benzyl,phenylpropyl, phenylbutyl and the like.

Ar is preferably an aryl radical which is unsubstituted or mono- orpolysubstituted by A, Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂,NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)_(w)A and/or OOCR⁶, andin particular phenyl, naphthyl or biphenyl, each of which isunsubstituted or substituted as above.

Het is preferably a saturated, unsaturated or aromatic mono- or bicyclicheterocyclic radical which is unsubstituted or mono- or polysubstitutedby A, Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂,NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)WA and/or OOCR⁶. Het is preferably a radicalwhich is unsubstituted or substituted as described above, selected from1-piperidyl, 1-piperazyl, 1-(4-methyl)piperazyl,4-methylpiperazin-1-ylamine, 4-morpholinyl, 1-pyrrolidinyl,1-pyrazolidinyl, 1-(2-methyl)pyrazolidinyl, 1-imidazolidinyl or1-(3-methyl)imidazolidinyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl,isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or3-pyrazinyl.

The radical Z is preferably a 5- or 6-membered, polyethylenicallyunsaturated or aromatic carbocyclic radical, which may be mono- orpolysubstituted, preferably mono- to trisubstituted, where thesubstituents are selected, independently of one another, from themeanings of R⁴ other than H, or are preferably selected from A, inparticular alkyl having from 1 to 6 carbon atoms, alkoxy having from 1to 6 carbon atoms and alkoxyalkyl having from 2 to 6 carbon atoms, Hal,in particular F and Cl, NO₂, OR⁶, N(R⁶)₂, CN, COOR⁶, CON(R⁶)₂, NR⁶COR⁶,NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)_(w)A, OOCR⁶ and C(NH)NOH.Examples of carbocyclic radicals Q are cyclopentadienyl,cyclohexadienyl, phenyl, naphthyl, in particular 1-naphthyl and2-naphthyl, and biphenyl, each of which may be substituted as describedabove/below. The carbocyclic radical Z is preferably phenyl andparticularly preferably substituted phenyl, in particular 4-alkylphenyl,such as 4-tolyl (4-methylphenyl), 4-alkoxyphenyl, such as4-methoxyphenyl, 3,4-dialkoxyphenyl, such as 3,4-dimethoxyphenyl and3,4-methylenedioxyphenyl, and 4-halophenyl, such as 4-fluorophenyl and4-chlorophenyl.

The radical Z is alternatively preferably a 5- or 6-membered,polyethylenically unsaturated or aromatic heterocyclic radical, whichmay contain from 1 to 4 heteroatoms, selected, independently of oneanother, from N, O and S, and may be mono- or polysubstituted,preferably mono- to trisubstituted, where the substituents are selected,independently of one another, from the meanings of R⁴ other than H, orare preferably selected from A, in particular alkyl having from 1 to 6carbon atoms, alkoxy having from 1 to 6 carbon atoms and alkoxyalkylhaving from 2 to 6 carbon atoms, Hal, in particular F and Cl, NO₂₁ OR⁶,N(R⁶)₂, CN, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶,SO₂NR⁶, S(O)_(w)A, OOCR⁶ and C(NH)NOH. Examples of heterocyclic radicalsQ are furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxopyridyl,thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl,benzo[1,4]dioxoinyl, 2,3-dihydrobenzo[1,4]dioxinyl, benzothiadiazolyi,chromenyl, 2-oxochromenyl, indolyl and indazolyl, each of which may besubstituted as described above/below. The heterocyclic radical Z isparticularly preferably optionally substituted furanyl, thiophenyl,pyrrolyl, pyridyl, pyridazyl, pyrazolyl, pyrazinyl, pyrimidyl,benzofuranyl, 2-oxo-chromenyl, indolyl, benzothiadiazolyl, quinolinyl,2,3-dihydrobenzo[1,4]dioxinyl and benzo[d]isothiazolyl.

The present invention preferably relates to compounds of the formula Ias described above in which R¹, p, E, G and Z have the meanings givenabove and below and in which

-   -   A is straight-chain alkyl having from 1 to 4 carbon atoms or        branched alkyl having from 3 to 6 carbon atoms, and    -   D-E is R²C═CR⁴ or R²R³C—CR⁴R⁵, in particular R²C═CR⁴ in which        R², R³ and R⁵ are selected, independently, from H, A and        cycloalkyl having from 3 to 7 carbon atoms, and R⁴ is Hal,        CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶,        (CH₂)_(n)CON(R⁶)₂, (CH₂)_(n)NR⁶COR⁶, (CH₂)_(n)NR⁶CON(R⁶)₂,        (CH₂)_(n)NR⁶SO₂A, (CH₂)_(n)SO₂N(R⁶) (CH₂)_(n)S(O)_(w)A,        (CH₂)_(n)OOCR⁶, (CH₂)_(n)COR⁶, (CH₂)_(n)CO(CH₂)_(m)Ar,        (CH₂)_(n)CO(CH₂)_(m)Het, (CH₂)_(n)COO(CH₂)_(m)Ar,        (CH₂)_(n)COO(CH₂)_(m)Het, (CH₂)_(n)OR⁶, (CH₂)_(n)O(CH₂)_(m)Ar,        (CH₂)_(n)O(CH₂)_(m)Het, (CH₂)_(n)SR⁶, (CH₂)_(n)S(CH₂)_(m)Ar,        (CH₂)_(n)S(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)(CH₂)_(m)Ar,        (CH₂)_(n)N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar,        (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het,        (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Ar,        (CH₂)_(n)N(R⁶)CO(CH₂)_(m)Ar, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Het,        (CH₂)_(n)N(R⁶)CO(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)₂, (CH₂)_(n)OCOR⁶,        (CH₂)_(n)OC(O)N(R⁶)₂, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar,        (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het, (CH₂)_(n)NR⁶COOR⁶,        (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar, (CH₂)_(n)NR⁶COO(CH₂)_(m)Het,        (CH₂)_(n)N(R⁶)CH₂CH₂OR⁶, (CH₂)_(n)N(R⁶)CH₂CH₂OCF₃,        (CH₂)_(n)N(R⁶)C(R⁶)HCOOR⁶, (CH₂)_(n)N(R⁶)CH₂COHet,        (CH₂)_(n)N(R⁶)CH₂Het, (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)CH₂COOR⁶,        (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)₂, CH═CHCOOR⁶, (CH₂)_(n)N(COOR⁶)COOR⁶,        (CH₂)_(n)N(CONH₂)COOR⁶, (CH₂)_(n)N(CONH₂)CONH₂,        (CH₂)_(n)N(CH₂COOR⁶)COOR⁶, (CH₂)_(n)N(CH₂CONH₂)COOR⁶,        (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR⁶COR⁶, (CH₂)_(n)CHR⁶COOR⁶        or (CH₂)_(n)CHR⁶CH₂OR⁶ and in particular Hal, CH₂Hal, CH(Hal)₂,        C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶ (CH₂)_(n)CON(R⁶)₂,        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)A,    -   m is 0, 1, 2, 3, 4 or 5 and    -   n is 0, 1, 2 or 3 and        -   in particular 0 or 1;    -   X¹ is (CHR⁷)_(g) or Q-(CHR⁸)_(k), in which    -   Q is selected from O, S, N—R⁶, (O—OCHR₇)_(g), (CHR⁷—O)_(g),        CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g), (CHR⁹CHR¹⁰—O), C—O, C—S, C═NR⁶,        C(OR⁶)(OR⁶), C(═O)O, OC(═O), OC(═O)O, C(═O)N(R⁶), N(R⁶)C(═O),        OC(O)N(R⁶), N(R⁶)C(═O)O, CH═N—O, CH═N—NR⁶, OC(O)NR⁶, NR⁶C(O),        S—O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   g is 1, 2, 3, 4, 5 or 6 and in particular 2, 3 or 4t    -   k is 0, 1, 2, 3, 4, 5 or 6 and in particular 1, 2 or 3, and    -   R⁷, R⁸, R⁹ and R¹⁰ are selected, independently, from the        meanings indicated for R² to R⁵;    -   X² is a bond or independently is (CHR⁷)_(g) or Q-(CHR⁸)_(k), in        which

Q is selected from O, S, N—R⁶, (O—CHR⁷)_(g), (CHR⁷—O)_(g),(O—CHR⁹CHR¹⁰)_(g), (CHR⁹CHR¹⁰—O)_(g), C═O, CH(OR⁶), C(═O)O, OC(═O),C(═O)N(R⁶), N(R⁶)C(═O), S═O, SO₂, SO₂NR⁶ and NR⁶SO₂, where g in X² ispreferably 1 or 2 and k in X² is preferably 0 or 1, and

-   -   R¹² is selected, independently, from the meanings of R⁴ other        than H and in particular, independently, is F, Cl, Br, I, CN,        NO₂, NH₂, CF₃, OCF₃, C(NH)NOH or SO₂CH₃,        and solvates and salts thereof.

The invention preferably relates to substituted indoles of the formulaIa

-   -   in which    -   R¹, D-E and Z are as defined above, and in which    -   X¹ is (CHR⁷)_(g) or (CHR⁷)_(h)-Q-(CHR⁸)_(k), in which    -   Q is selected from O, S, N—R⁶, (O—CHR⁷)_(g), (CHR⁷—O)_(g),        CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g), (CHR⁹CHR¹⁰—O)_(g), C═O, C═S, C═NR⁶,        CH(OR⁶), C(OR⁶)(OR⁶), C(═O)O, OC(═O), OC(═O)O, C(═O)N(R⁶),        N(R⁶)C(═O), OC(═O)N(R⁶), N(R⁶)C(═O)O, CH═N—O, CH═N—NR⁶,        OC(O)NR⁶, NR⁶C(O)O, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   g is 1, 2, 3, 4, 5 or 6,    -   h and k, independently of one another, are 0, 1, 2, 3, 4, 5 or        6, and    -   R⁶ is selected, independently, from H, A or cycloalkyl having        from 3 to 7 carbon atoms,    -   R⁷, R⁸, R⁹ and R¹⁰ are selected, independently, from the        meanings indicated for 2 to R⁵;    -   Y is CH, N, COR¹¹, CSR¹¹, an unsubstituted or substituted,        spiro-linked carbocyclic radical having from 5 to 7 carbon atoms        or an unsubstituted or substituted, spiro-linked, 5-, 6- or        7-membered heterocyclic radical having from 1 to 3 heteroatoms        selected from N, S or O,    -   R¹¹ is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar or cycloalkyl having from        3 to 7 carbon atoms,    -   X² is a bond or is selected, independently, from the meanings        indicated for X¹, and is preferably a bond or O, S, N—R⁷, CH₂ or        CH₂CH₂,    -   p, q and r, independently of one another, are 0, 1, 2 or 3    -   and    -   Hal is F, Cl, Br or I, and    -   R¹² and R¹³, independently of one another, are selected from the        meanings of R⁴ other than H and are preferably, independently of        one another, Hal, CN, NO₂, OR⁶, N(R⁶)₂, NO₂, CN, COOR⁶,        CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂NR⁶,        S(O)_(w)A, OOCR⁶ and/or C(NH)NOH,        and salts and solvates thereof preferably physiologically        tolerated salts and solvates thereof and in particular        physiologically tolerated salts thereof.

The sum of n and m is preferably greater than zero

In the compounds of the formula I, the E-N-G-X²-Z group is preferablyselected from groups of the formulae

or the thioamides thereofin which X² and Z are as defined above and below, and R′ is H, A,(CH₂)_(n)Het, (CH₂)_(n)Ar, cycloalkyl having from 3 to 7 carbon atoms orSO₂A.

In the compounds of the formula I, of the formula Ia and the compoundsof the formula III, the X²-Z group is preferably selected from thegroups

in which

-   -   R¹⁴ is selected, independently, from Hal, A, (CH₂)_(n)Het,        (CH₂)_(r)Ar, (CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het,        (CH₂)_(n)OR⁶, (CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het,        (CH₂)_(n)N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)(CH₂)_(m)Het,        (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar,        (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het,        (CH₂)_(n)N(R⁶)₂, (CH₂)_(n)NHOA, (CH₂)_(n)(R⁶)Het,        (CH₂)_(n)OCOR⁶, (CH₂)_(n)OC(O)N(R⁶)₂,        (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het,        (CH₂)_(n)NR⁶COOR⁶, (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar,        (CH₂)_(n)NR⁶COO(CH₂)_(m)Het, and in particular, independently of        one another, is Hal, NO₂, OR⁶, N(R⁶)₂, CN, COOR⁶, CON(R⁶)₂,        NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)_(w)A, OOCR⁶        and/or C(NH)NOH,    -   w is 0, 1, 2 or 3,    -   t is 0, 1, 2, 3, 4 or 5 and in particular 0, 1, 2 or 3, and    -   R′ is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar, cycloalkyl having from 3        to 7 carbon atoms or SO₂A.

If the X²-Z group is the

group, it is preferably selected from the groups

in which X² and R′ are as defined above/below.

In a preferred embodiment of the present invention, n is 0 or 1 and inparticular 0.

In a particularly preferred embodiment of the present invention, n inthe radicals R², R³, R⁴ and/or R⁵, preferably in the radicals R² and/orR⁴ and in particular in the radical R⁴ is 0.

Some preferred groups of compounds can be expressed by the followingsub-formulae Ia) to In), which conform to the formula I and/or to theformula Ia and in which the radicals not designated in greater detailhave the meaning indicated above/below, but in which

in Ia) R¹ is H or SO₂A and in particular H or SO₂—CH₃;in Ib) R¹ is H or SO₂A and in particular H or SO₂—CH₃;

-   -   D-E is R²C═COR⁴;        in Ic) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶,        (CH₂)_(n)CON(R⁶)₂(CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;        in Id) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;        in Ie) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A;        in If) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C—CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(,)COOR⁶, (CH₂)_(,)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(,)S(O)_(w)R⁶ and    -   R⁶ is H or A, and    -   n is 0 or 1;        in Ig) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is Hr alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂ (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is        -   Q-(CHR⁸)_(k), in which k is 1, 2 or 3;            in Ih) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C═O, C—S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂;        in Ii) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C═O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂, and    -   R⁷ and R⁸ are selected, independently of one another, from H and        A;        in Ij) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(PR⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C—O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   R⁷ and R⁸ are selected, independently of one another, from H and        A, and    -   Y is CH, COR¹¹, N or an unsubstituted or substituted,        spiro-linked, 5-, 6- or 7-membered heterocyclic radical having        from 1 to 3 heteroatoms selected from N, S or O,        in Ik) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C—CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶ (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, or 3 and Q is selected from O, S, N—R⁶, CONR⁶,        C═O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   R⁷ and R⁸ are selected, independently of one another, from H and        A,    -   Y is CH, COR¹¹, N or an unsubstituted or substituted,        spiro-linked, 5-, 6- or 7-membered heterocyclic radical having        from 1 to 3 heteroatoms selected from N, S or O; and    -   R¹¹ is H or A;        in II) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C═O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   R⁷ and R⁸ are selected, independently of one another, from H and        A,    -   Y is CH, COR¹¹, N or an unsubstituted or substituted,        spiro-linked, 5-, 6- or 7-membered heterocyclic radical having        from 1 to 3 heteroatoms selected from N, S or O,    -   R¹¹ is H or A, and    -   X² is CH₂, CH₂CH₂, HCOH, O, S, N—R⁶, CONR⁶, C═O or a bond;        in Im) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C═O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   R⁷ and R⁸ are selected, independently of one another, from H and        A,    -   Y is CH, COR¹¹, N or an unsubstituted or substituted,        spiro-linked, 5-, 6- or 7-membered heterocyclic radical having        from 1 to 3 heteroatoms selected from N. S or O,    -   R¹¹ is H or A, and    -   X² is CH₂, CH₂CH₂, HCOH, O, S, N—R⁶, CONR⁶, C═O or a bond, and    -   R¹² is selected, independently, from A, Hal, CN, NO₂, OR⁶,        N(R⁶)₂, COOR⁶, CON(R⁶)₂, COR⁶, SO₂N(R⁶)₂ and S(O)_(w)A;        in In) R¹ is H or SO₂A and in particular H or SO₂—CH₃;    -   D-E is R²C═CR⁴,    -   R² is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R;    -   R⁴ is H, alkyl having from 1 to 3 carbon atoms, alkoxyalkyl        having from 2 to 5 carbon atoms, Hal, CH₂Hal, CH(Hal)₂, O(Hal)₃,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)COOR⁶, (CH₂)_(n)CON(R⁶)₂        (CH₂)_(n)SO₂N(R⁶)₂ or (CH₂)_(n)S(O)_(w)R⁶ and    -   R⁶ is H or A,    -   n is 0 or 1,    -   X¹ is (CHR⁷)_(g), in which g is 2, 3 or 4, or is Q-(CHR⁸)_(k),        in which k is 1, 2 or 3 and Q is selected from O, S, N—R⁶,        CONR⁶, C═O, C═S, S═O, SO₂, SO₂NR⁶ and NR⁶SO₂,    -   R⁷ and R⁸ are selected, independently of one another, from H and        A,

Y is CH, COR¹¹, N or an unsubstituted or substituted, spiro-linked, 5-,6- or 7-membered heterocyclic radical having from 1 to 3 heteroatomsselected from N, S or O,

-   -   R¹¹ is H or A, and    -   X² is CH₂, CH₂CH₂, HCOH, O, S, N—R⁶, CONR⁶, C═O or a bond,    -   R¹² is selected, independently, from A, Hal, CN, NO₂, OR⁶,        N(R⁶)₂, COOR⁶, CON(R⁶)₂, COR⁶, SO₂N(R⁶)₂ and S(O)_(w)A, and    -   R¹⁴ is selected, independently, from A, Hal, CN, NO₂, OR⁶,        N(R⁶)₂, COOR⁶, CON(R⁶)₂, COR⁶, SO₂N(R⁶)₂ and S(O)_(w)A.

In a preferred embodiment of the present invention, the radical R² inthe sub-formulae Ia) to In) is H, A, in particular alkyl having from 1to 4 carbon atoms or O-alkyl having from 1 to 4 carbon atoms, Hal, inparticular F or Br, CN, NO₂ NH₂, CF₃, OCF₃ SO₂CH₃, COOR⁶ or CON(R⁶)₂,particularly preferably H, alkyl having from 1 to 4 carbon atoms or CN;and R⁴ is H, A, in particular alkyl having from 1 to 4 carbon atoms orO-alkyl having from 1 to 4 carbon atoms, Hal, in particular F or Br, CN,NO₂ NH₂, CF₃, OCF₃ SO₂CH₃, COOR⁶ or CON(R⁶)₂, particularly preferablyCN. In this preferred embodiment, R² is H or A in particular if R⁴ isHal, NO₂ NH₂, CF₃, OCF₃ SO₂CH₃, COOR⁶ or CON(R⁶)₂ and in particular isCN. In this preferred embodiment, the compound of the formula I and/orof the formula Ia preferably has one or two substituents R¹² andparticularly preferably no substituents R¹². In this preferredembodiment, the compound of the formula I and/or of the formula Iaparticularly preferably has one or two substituents R¹³ and veryparticularly preferably no substituents R³. In this preferredembodiment, the compound of the formula I and/or of the formula Iapreferably has no, one or two substituents R⁴ and in particular one ortwo substituents R¹⁴. If the compound of the formula I and/or of theformula Ia has one or two substituents R¹⁴, these are preferablyselected from F, Cl, Br, I, CN, CF₃ and OCF₃ and in particular areselected from F, CF₃ and OCF₃.

In a specific and preferred embodiment, the present invention relates toa compound of the formula I and/or of the formula Ia and in particular acompound of the sub-formulae Ia) to In) in which D-E is R²C═CR⁴, R² is Hor methyl and R⁴ is CN, and solvates and salts thereof.

In a further specific and preferred embodiment, the present inventionrelates to a compound of the formula I and/or of the formula Ia and inparticular a compound of the sub-formulae Ia) to In) in which X¹ isCH₂CH₂ (i.e. is (CHR⁷)_(g) in which R⁷ is H and g is 2), CH₂CH₂CH₂ (i.e.is (CHR⁷)_(g) in which R⁷ is H and g is 3) or OCH₂CH₂ (i.e. is(CHR⁷)_(h)-Q-(CHR⁸)_(k) in which h is 0, R⁸ is H and k is 2), andsolvates and salts thereof.

In a further specific and preferred embodiment, the present inventionrelates to a compound of the formula I and/or of the formula Ia and inparticular a compound of the sub-formulae Ia) to In) in which Y is CH,CHOH (i.e. is COR¹¹ in which R¹¹ is H) or N and in particular is CH, andsolvates and salts thereof.

In a further specific and preferred embodiment, the present inventionrelates to a compound of the formula I and/or of the formula Ia and inparticular a compound of the sub-formulae Ia) to In) in which Y is anunsubstituted or substituted, spiro-linked, 5-, 6- or 7-memberedheterocyclic radical having from 1 to 3 heteroatoms selected from N, Sor O, and particularly preferably an unsubstituted or substituted,spiro-linked, 5-membered heterocyclic radical having 2 heteroatoms,preferably 2 N atoms. In this embodiment, the spiro-linked heterocyclicradical preferably has, as one substituent, a double-bonded oxygenradical (═O), i.e. an oxo substituent, or a double-bonded sulfur radical(═S), i.e. a thioxo substituent. The spiro-linked heterocyclic radicalparticularly preferably has, as one substituent, an oxo substituent. Thespiro-linked heterocyclic radical is very particularly preferablyselected from structures of the formulae

in which X², Z and R′ are as defined above/below, and Y′ is thespiro-linking carbon atom of the spiro-linked heterocyclic radical. Inthis embodiment, X² is particularly preferably a bond. In particular,the spiro-linked heterocyclic radical is therefore selected fromstructures of the formulae

in which X², Z and R′ are as defined above/below, and Y′ is thespiro-linking carbon atom of the spiro-linked heterocyclic radical.

In a further specific and preferred embodiment, the present inventionrelates to a compound of the formula I and/or of the formula Ia and inparticular a compound of the sub-formulae Ia) to In) in which X² is CH₂(i.e. is (CHR⁷)_(g) in which R⁷ is H and g is 1), CH₂CH₂ (i.e. is(CHR⁷)_(g) in which R⁷ is H and g is 2), OCH₂ (i.e. is(CHR⁷)_(h)-Q-(CHR⁸)_(k) in which Q is O, h is O, R⁸ is H and k is 1), O(i.e. is (CHR⁷)_(h)-Q-(CHR⁸)_(k) in which Q is O and h and k are 0), S(i.e. is (CHR⁷)_(h)-Q-(CHR⁸)_(k) in which Q is S and h and k are 0), C═O(i.e. is (CHR⁷)_(h)-Q-(CHR⁸)_(k) in which Q is C═O and h and k are 0),or NH (i.e. is (CHR⁷)_(h)-Q-(CHR⁸)_(k) in which Q is N—R⁶, R⁶ is H and hand k are 0), particularly preferably is CH₂, O, NH and CHOH and inparticular is CH₂ or O, and solvates and salts thereof.

In a further specific and preferred embodiment, the present inventionrelates to a compound of the formula I and/or of the formula Ia and inparticular a compound of the sub-formulae Ia) to In) in which X² is achemical bond between the groups Y and Z. In this embodiment, the Y—X²-Zgroup is thus the Y-Z group.

In a further specific and preferred embodiment, the E-N-G-X²-Z group inthe compounds of the formula I is a radical of the formula

In a further specific and preferred embodiment, the E-N-G-X²-Z group inthe compounds of the formula I is a radical of the formula

or a radical of the formula

In a further specific and preferred embodiment, the E-N-G-X²-Z group inthe compounds of the formula I is a radical of the formula

In a particularly preferred embodiment, the present invention relates toa compound of the formula I and/or of the formula Ia and in particular acompound of the sub-formulae Ia) to In) which comprises the features ofone or more of the embodiments described above and in particular thefeatures of all embodiments described above or the features of allembodiments described above which are not mutually exclusive.

In the compounds of the formula I and/or of the formula Ia, X¹ is,relative to the indole nitrogen, preferably in the 4-, 5- or 6-position,particularly preferably the 4-position or 6-position and in particularin the 4-position of the indole radical (in accordance with IUPACnomenclature for indole systems).

In the compounds of the formula I and/or of the formula Ia, thesubstituents R¹⁴ are preferably in the ortho- and/or para-position,relative to Z.

The present invention therefore particularly preferably relates tocompounds of the formulae Iα, Iβ and I_(χ)

in which R¹, R², Q, Y, X², R¹⁴ and t are as defined above and inparticular in the above sub-formulae Ia) to In) and/or the aboveembodiments, and compounds of the formulae Iδ, Iε and Iζ

in which R¹, R², Y, X² and Z are as defined above and in particular inthe above sub-formulae Ia) to In) and/or the above embodiments.

In the compounds of the formulae Iα, Iβ and I_(χ), (R¹⁴)_(t) isparticularly preferably a fluorine substituent in the para-position, twofluorine substituents, one of which is in the para-position and one isin the meta-position, relative to Z, or CONH₂ in the para-position.Furthermore, in the formulae Iα, Iβ and I_(χ), R¹ and/or R² arepreferably H, Q is CH₂ and Y is CH and X² is O or CH₂.

In the compounds of the formulae Iδ and Iε, the group Y is particularlypreferably N or CH. In the compounds of the formula Iζ, the group Z isparticularly preferably substituted and in particular unsubstitutedphenyl.

In the compounds of the formula Iδ, the group Y—X²-z is preferably aradical of the formula

or a radical of the formula

In the compounds of the formula Iε, the group Y-Z is particularlypreferably a radical of the formulae

or a radical of the formulae

In a very particularly preferred embodiment of the present invention,the compounds of the formula I and/or of the formula Ia are selectedfrom

-   6-{3-[4-(4-Fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   6-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   6-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   4-{3-[4-(4-Fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   4-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   4-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   5-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   5-{3-[4-(4-Fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   5-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;

-   5-{3-[4-(4-Cyanophenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{4-[3-(3-Cyano-1H-indol-6-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide

-   5-{3-[4-(2-Oxo-2H-chromen-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{4-[3-(3-Cyano-1H-indol-4-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide

-   5-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide

-   5-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-1-methanesulfonyl-1H-indole-3-carbonitrile

-   5-[3-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-1H-indole-3-carbonitrile

-   5-[3-(4-Benzo[1,2,5    ]thiadiazol-4-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile

-   3-{1-[3-(3-Cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carboxamide

-   5-[3-(4-Quinolin-8-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile

-   5-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   1-Methanesulfonyl-5-[3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-1H-indole-3-carbonitrile

-   5-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(1H-Indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile

-   3-{1-[3-(3-Cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carbonitrile

-   5-{3-[4-(6-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(4-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-[3-(4-Benzo[d]isothiazol-3-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile

-   4-{1-[3-(3-Cyano-1H-indol-6-yl)propyl]piperidin-4-yloxy}benzamide

-   6-{3-[4-(2-Cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   6-{3-[4-(4-Cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   6-{3-[4-(4-Cyano-2-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   4-[3-(4-Pyrazol-1-ylmethyl-1-piperidyl)propyl]-1H-indole-3-carbonitrile

-   N-(6-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)acetamide

-   5-{3-[(Pyridin-3-ylmethyl)amino]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-[3-(4-Pyrimidin-2-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile

-   5-{3-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(3-Methoxyphenyl)-3-methylpiperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   5-{3-[4-(1-Methyl-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   N-(4-{1-[3-(3-Cyano-1H-indol-5-yl)propyl]piperidin-4-ylmethyl}-phenyl)acetamide

-   5-{3-[4-(4-Pyridin-3-ylthiazol-2-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   Ethyl    2-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-thiazole-4-carboxylate

-   5-{3-[3-(2-Oxopyrrolidin-1-yl)propylamino]propyl}-1H-indole-3-carbonitrile

-   Ethyl    (6-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)carbamate

-   5-{3-[4-(3-Amino-2-oxo-2H-chromen-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile

-   Methyl    (6-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)carbamate

-   2-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-thiazole-4-carboxamide

-   4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-thiocarboxamide    and salts and solvates thereof preferably physiologically tolerated    salts and solvates thereof and in particular physiologically    tolerated salts thereof.

Depending on the choice of the substituents and radicals describedabove, the compounds according to the invention can have one or morechiral centres, in particular one or more chiral carbon atoms. If acompound of defined composition according to the invention has one ormore chiral centres, this compound of defined composition can exist inthe form of various stereoisomers. The present invention relates to allpossible such stereoisomers of compounds according to the invention,which can exist either as individual, stereochemically uniform compoundsor as mixtures of two or more stereochemically uniform compounds. In thecase of mixtures of two or more stereoisomers, the individualstereoisomers may be present in different or identical proportions. Inmixtures of two stereoisomers which are present in identical proportionsand represent optical antipodes, the term racemic mixtures is used.Racemic mixtures of compounds of the formula I are likewise asubject-matter of the present invention.

The compounds of the formula I and also the starting materials for thepreparation thereof are, in addition, prepared by methods known per se,as described in the literature (for example in the standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials, for example the compounds of the formula IIand/or III, can, if desired, also be formed in situ by not isolatingthem from the reaction mixture, but instead immediately converting themfurther into the compound of the formula I.

The compound of the formula I can preferably be obtained by reactingcompounds of the formula II with benzylpiperidine, phenoxypiperidine orderivatives thereof, in particular 4-(4-fluorobenzyl)piperidine,4-(2,4-difluorobenzyl)piperidine or 4-(4-fluorophenoxy)piperidine.

The starting compounds of the formula II are generally novel. However,they can be prepared by methods known per se. The starting compounds ofthe formula III are either novel or known from the literature orcommercially available. In any case, however, they can be prepared bymethods known per se.

In the compounds of the formula II, L¹ is preferably Cl, Br, I, OH or areactively modified OH group, in particular a reactively esterified OHgroup, such as an alkylsulfonyloxy group having 1-6 carbon atoms(preferably methylsulfonyloxy) or arylsulfonyloxy group having 6-10carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or a diazoniumgroup.

In the compounds of the formula III, L² is preferably H or a group whichactivates the amino function, for example a metal ion. Suitable metalions are, in particular, alkali metal, alkaline earth metal or aluminiumions. Preferred metal ions are alkali metal ions, in particular Li, Naor K. In the case of polyvalent metal ions, a complex of metal ion andtwo or more compounds of the formula III often forms, where the complexgenerally comprises stoichiometrically as many compounds of the formulaIII as corresponds to the valency of the metal ion.

The reaction of the compounds of the formula II with compounds of theformula III is generally carried out in an inert solvent, preferably inthe presence of an acid-binding agent. Suitable acid-binding agents areall bases which are usual in synthetic organic chemistry, both inorganicand organic bases, preferably organic bases. Examples of suitableorganic bases are triethylamine, diisopropylamine (DIPEA),dimethylaniline, pyridine and quinoline. The addition of an inorganicbase, such as, for example, an alkali or alkaline earth metal hydroxide,carbonate or bicarbonate, or another salt of a weak acid of the alkalior alkaline earth metals, preferably of potassium, sodium, calcium orcaesium, may also be favourable.

The reaction time is, depending on the conditions used, between a fewminutes and 14 days, and the reaction temperature is between about −30°and 180°, normally between −20° and 140°, preferably between −10° and130° and in particular between about 0° and about 120° In many cases, itis favourable to carry out the reaction of a starting compound of theformula II with a starting compound of the formula III at comparativelyhigh temperatures, for example at a temperature in the range from 70° to130°, preferably from 80° to 120° and in particular from 90° to 110°,for example at about 100°. In a reaction in this temperature range, itis in many cases favourable to use an organic base, such astriethylamine or diisopropylamine, or preferably an inorganic base, suchas sodium hydroxide, sodium carbonate and in particular sodiumhydrogencarbonate.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, water, ormixtures of the said solvents.

The starting compounds of the formula II, in particular those in which Xis (CHR⁷)₃ and preferably a propylene radical, i.e. CH₂CH₂CH₂, canadvantageously be prepared in a multistep synthesis sequence whichstarts from a compound of the formula VI

In a first step, the ester group COOA of the compound of the formula VIis reduced to a hydroxymethyl group CH₂—OH, for example using hydrides,preferably complex hydrides, such as lithium aluminium hydride. Thisgives a hydroxymethyl derivative of the formula VII

which can be converted in a second step using an oxidant, such as, forexample, manganese dioxide (MnO₂), into an aldehyde derivative of theformula VIII

The aldehyde derivative of the formula VIII be condensed in a thirdreaction step with an acetic acid derivative CH₃—COOA, preferably ethylacetate and in particular methyl acetate (aldol condensation). Thecondensation is preferably carried out under basic conditions, forexample using alkoxides, such as sodium methoxide or sodium ethoxide, asbase. This third step gives an acrylate derivative of the formula IX

which can be hydrogenated in a fourth step to give a compound of theformula X

for example in a hydrogen atmosphere in the presence of a platinum metalcatalyst, such as, for example, palladium/carbon. The compound of theformula X can subsequently be reduced in a fifth step to an alcoholderivative of the formula XI

Suitable reducing agents for this step are, for example, metal or boronhydrides and in particular complex hydrides, such as lithium aluminiumhydride, and so-called deactivated complex hydrides, such asLiAl(OR)_(x)H_(4-x), in which X is 1, 2 or 3 and R are alkyl radicalshaving from 1 to of carbons. A deactivated complex hydride which issuitable for this reduction is commercially available under the nameVitride. The use of the so-called deactivated complex hydrides isparticularly advantageous if it is desired to achieve selectivereduction of the COOA group in the compound X to an alcohol group as inthe formula XI in the presence of other groups which can be reduced byconventional hydrides, such as lithium aluminium hydride, such as, forexample, nitrile groups. The compound XI is an example of a compound ofthe formula II in which X is CH₂CH₂CH₂ and L¹ is OH. A compound of theformula XI is preferably converted into a compound of the formula XII

in which the OH group is reactively esterified, for example by reactionwith alkyl- or arylsulfonyl chlorides, preferably in the presence of abase, such as, for example, alkylamines and in particular triethylamineor diisopropylamine. The compounds of the formula XI or preferably ofthe formula XII are subsequently reacted with a compound of the formulaIII in which L² is preferably H to give a compound of the formula I,preferably in the presence of a base, such as, for example, alkali metalhydroxides, alkali metal carbonates and in particular alkali metalhydrogencarbonates.

For the preparation of compounds of the formula I in which D-E isR²C═CR⁴ and R² and/or R⁴ is CN, it is advantageous to start fromcompounds of the formula VI in which D-E is R²C═COR⁴ and R² and/or R⁴ isH, and to convert these firstly, as described above, into compounds ofthe formulae VIII, VII VIII and IX in which D-E is R²C═CR⁴ and R² and/orR⁴ is H. The conversion of R² and/or R⁴ from H into CN is thenpreferably carried out by firstly allowing dimethylformamide to reactwith phosphoryl chloride, adding a compound of the formula IX in whichD-E is R²C═CR⁴ and R² and/or R⁴ is H and in particular a compound of theformula IXa in which D-E is R²C═CR⁴ and R² and R⁴ is H, allowing thereaction mixture to react, preferably at a temperature between 50 and150° C. and in particular from 80 to 130° C., preferably for a time inthe range from ten minutes to two hours and in particular from 30 to 90minutes. The reaction mixture is subsequently reacted withhydroxylammonium chloride (=hydroxylamine hydrochloride). The reactionwith hydroxylammonium chloride is preferably carried out in atemperature range as described above and for a period of from 2 to 60minutes and in particular from 5 to 30 minutes. For work-up, thereaction mixture is preferably hydrolysed, and the compound of theformula IX in which D-E is R²C═CR⁴ and R² and/or R⁴ is CN, or, if acompound of the formula IXa has been employed, the compound of theformula IXb in which D-E is R²C═CR and R² is H and R⁴ is CN is isolatedby conventional methods which are familiar to the person skilled in theart.

The above process is particularly suitable for the conversion ofcompounds of the formula IX in which D-E is R²C═CR⁴ and R² and R⁴ is Hinto compounds of the formula IX in which D-E is R²C═CR⁴, R² is H and R⁴is CN.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

The compounds according to the invention can be used as therapeuticagents, diagnostic agents and/or cosmetics or together with one or moreactive ingredients other than the compounds according to the inventionand/or adjuvants in therapeutic agents, diagnostic agents and/orcosmetics. The compounds according to the invention are usually employedin the form of pharmaceutical, diagnostic and/or cosmetic formulations.Formulations of this type and processes for the preparation thereof areknown to the person skilled in the art.

Examples of formulations of this type are suspensions, emulsions,solutions, liposomes, salts, pastes, biodegradable polymers,nanoparticles, tablets, coated tablets, sugar-coated tablets,film-coated tablets, capsules, pills, granules, powders, aerosols, dropsor sprays comprising at least one compound according to the invention.

The compounds according to the invention or formulations which compriseat least one compound according to the invention can be administered tohumans or animals, for example locally or systemically and in particularorally, intravenously, intraperitoneally, subcutaneously, transdermally,nasally, buccally and/or iontophoretically.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of pharmaceutical preparations, in particular bynon-chemical methods. They can be converted here into a suitable dosageform together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and, if desired, in combination with one or morefurther active ingredients.

The invention furthermore relates to pharmaceutical preparationscomprising an effective amount of at least one of the compounds of theformula I and/or one of its physiologically acceptable salts thereof.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration or administration in the form of an inhalation spray anddo not react with the novel compounds, for example water, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatine, carbohydrates, such as lactose or starch,magnesium stearate, talc or Vaseline. Suitable for oral administrationare, in particular, tablets, pills, sugar-coated tablets, capsules,powders, granules, syrups, juices or drops, suitable for rectaladministration are suppositories, suitable for parenteral administrationare solutions, preferably oil-based or aqueous solutions, furthermoresuspensions, emulsions or implants, and suitable for topical applicationare ointments, creams or powders. The novel compounds may also belyophilised and the resultant lyophilisates used, for example, toprepare injection preparations. The preparations indicated may besterilised and/or comprise adjuvants, such as lubricants, preservatives,stabilisers and/or wetting agents, emulsifying agents, salts formodifying the osmotic pressure, buffer substances, colorants andflavours and/or a plurality of further active ingredients, for exampleone or more vitamins.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronised form, in which case one or more additional physiologicallytolerated solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

The present invention therefore relates to a process for the preparationof pharmaceutical compositions which is characterised in that a compoundof the formula I according to claim 1 and/or one of its physiologicallyacceptable salts and/or solvates is converted into a suitable dosageform together with at least one solid, liquid or semi-liquid excipientor adjuvant.

The compounds of the formula I and/or physiologically acceptable saltsthereof can be used as excitatory amino acid antagonists for combatingdiseases, in particular for combating neurodegenerative diseases,including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, cerebral ischaemia,infarction or psychoses.

The present invention therefore relates to the use of compounds of theformula I according to claim 1 and/or physiologically acceptable saltsor solvates thereof for the preparation of a medicament for theprophylaxis and/or treatment of schizophrenia, depression, dementia,Parkinson's disease, Alzheimer's disease, Lewy bodies dementia,Huntington's disease, Tourette's syndrome, anxiety, learning and memoryimpairment, neurodegenerative diseases and other cognitive impairments,as well as nicotine dependence and pain.

In general, the compounds according to the invention can be administeredanalogously to other known compounds having a similar action profile,such as, for example, ifenprodil, preferably in doses between about 0.05and 500 mg, in particular between 0.5 and 100 mg, per dosage unit. Thedaily dose is preferably between about 0.01 and 2 mg/kg of body weight.However, the specific dose for each patient depends on a wide variety offactors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and method of administration, on the excretion rate, medicamentcombination and severity of the particular disease to which the therapyapplies. Parenteral administration is preferred. Oral administration isparticularly preferred.

The compounds according to the invention exhibit an advantageous actionprofile while being comparatively easy to prepare. Thus, in receptorbinding tests, compounds according to the invention exhibit an affinityto the ifenprodil binding site of the NMDA receptor, even in nanomolarconcentrations. In addition, the compounds according to the invention,as polyamine antagonists which preferentially bind selectively to theNR2B receptor of the NMDA sub-receptor class, are preferablydistinguished by no or and only very slight elongation of the QT segmentin the electrocardiogram.

The compounds of the formula I and pharmaceutically usable prodrugs,derivatives, solvates, stereoisomers and salts thereof are particularlypreferably suitable for the treatment of diseases of the central nervoussystem, such as states of tension, depression, anxiety states,schizophrenia, gastrointestinal tract disorders, nausea, tardivedyskinesia, Parkinson's disease and/or psychoses and of side effects inthe treatment of hypertonia (for example using u,-methyldopa). Thecompounds can furthermore advantageously be used in endocrinology andgynaecology, for example for the therapy of acromegaly, hypogonadism,secondary amenorrhoea, premenstrual syndrome, undesired puerperallactation, furthermore for the prophylaxis and therapy of cerebraldisorders (for example migraine), in particular in geriatrics, in asimilar way to certain ergot alkaloids.

The compounds according to the invention can also very particularlypreferably be employed as therapeutic agents for combating theconsequences of cerebral infarction (apoplexia cerebri), such as strokesand cerebral ischaemia, and for the treatment of brain and spinal cordtrauma.

The compounds according to the invention are particularly suitable asmedicament active ingredients for anxiolytics, antidepressants,antipsychotics, neuroleptics, antihypertonics and/or for positivelyinfluencing obsessive-compulsive disorder (OCD), sleeping disorders,tardive dyskinesia, learning disorders, age-related memory disorders,eating disorders, such as bulimia, and/or sexual dysfunctions.

For the above-mentioned indications/areas of application, preferably forthe indications/areas of application mentioned in the two precedingparagraphs, the substances according to the invention are generallyadministered analogously to known commercially available preparations(for example citalopram and fluoxetine), preferably in doses of betweenabout 0.2 and 500 mg, in particular between 0.2 and 50 mg, per dosageunit. The daily dose is preferably between about 0.001 and 10 mg/kg ofbody weight. The low doses are between about 0.2 and 500 mg, inparticular between 0.2 and 50 mg, per dosage unit. The low doses (fromabout 0.2 to 1 mg per dosage unit; from about 0.001 to 0.005 mg/kg ofbody weight) are particularly suitable for use as migraine agents, forthe other indications, doses of between 10 and 50 mg per dosage unit arepreferred. However, the specific dose for each particular patientdepends on a very wide variety of factors, for example on the efficacyof the specific compound employed, on the age, body weight, generalstate of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, medicament combination andseverity of the particular disease to which the therapy applies. Oraladministration is preferred for the above-mentioned indications.

Above and below, all temperatures are given in ° C. In the followingexamples, “conventional work-up” means that water is added if necessary,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, if necessary theorganic phase is dried, for example over sodium sulfate, the organicphase is evaporated, and the residue obtained is purified bychromatography, for example on silica gel, and/or by crystallisation.

EXAMPLE 1 Preparation of4-{3-[4-(fluorobenzyl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile(=EMD 432517) 1.1. Step a: preparation of 4-hydroxymethylindole (2)

-   -   A solution of 25 g of methyl 4-indolecarboxylate (1) in 200 ml        of tetrahydrofuran is added to a suspension of LiAlH₄ in 100 ml        of tetrahydrofuran under a protective-gas atmosphere (N₂) at        such a rate that the temperature of the reaction mixture does        not exceed 40° C. When the addition is complete, the reaction        mixture is stirred at room temperature (25° C.) for        approximately two further hours until the methyl        4-indolecarboxylate has reacted completely. The reaction mixture        is subsequently hydrolysed by addition of ice-water (about 100        ml), and the hydrolysate is filtered through a bed of        kieselguhr. After the tetrahydrofuran has been removed by        distillation, the aqueous phase obtained is extracted with ethyl        acetate. The organic phase obtained is dried over magnesium        sulfate and evaporated, giving 16.0 g (76% of theory) of a        pale-beige crystalline residue of 4-hydroxymethylindole (2).

1.2. Step b: Preparation of 4-formylindole (3)

-   -   Manganese dioxide (MnO₂) is added slowly with stirring to a        solution of 74 g of 4-hydroxymethylindole (2) in 3 litres of        dichloromethane, and the mixture is subsequently stirred at room        temperature for 72 hours. The reaction mixture is subsequently        filtered through kieselguhr, and the filtrate is evaporated. The        crystalline residue obtained is stirred with cyclohexane and        filtered under reduced pressure. Drying gives 63 g (86% of        theory) of crystalline 4-formylindole (a).

1.3. Step c: Preparation of methyl 3-(1H-indol-4-yl)acrylate (4)

-   -   48 g of sodium methoxide are added to 300 ml of tetrahydrofuran        with stirring at 5° C. under a protective gas (N₂), the        suspension is cooled to 0° C., 70 ml of methyl acetate are added        dropwise at from 0 to 3° C., and the mixture is stirred at this        temperature for a further 45 minutes. A solution of 43 g of        4-formylindole (a) in 300 ml of tetrahydrofuran is subsequently        added with stirring, during which the temperature does not        exceed 3° C. The mixture is subsequently stirred at room        temperature for a further two hours. For work-up, the reaction        mixture is evaporated, and the residue is dissolved in methyl        acetate and extracted with water. The organic phase obtained is        dried, the solvent is removed under reduced pressure, and the        residue is purified by chromatography on silica gel, giving 35 g        (59% of theory) of a pale-beige crystalline residue of methyl        3-(1H-indol-4-yl)acrylate (4).

1.4. Step d: Preparation of Indolecarbonitrile 5

-   -   Phosphoryl chloride is added dropwise with cooling in an ice        bath to 100 ml of dimethylformamide at such a rate that the        temperature of the mixture is from about 20 to 30° C. A solution        of 25 g of 3-(1H-indol-4-yl)acrylic acid in 100 ml of        dimethylformamide is subsequently added dropwise at room        temperature, during which the temperature rises to 60° C. The        mixture is subsequently stirred at 125° C. for one hour. A warm        solution of 17.2 g of hydroxylammonium chloride in 100 ml of        dimethylformamide is then added, and the mixture is stirred at        120° C. for a further 15 minutes. The reaction mixture is cooled        to room temperature and added dropwise with stirring to        ice-water, whereupon beige crystals precipitate. The mixture is        stirred for a further two hours and filtered, and the        crystalline residue is dried overnight at 120° C. under reduced        pressure, giving 23.5 g (84% of theory) of a pale-beige        crystalline residue of indolecarbonitrile 5.

1.5. Step e: Preparation of Compound 6

-   -   5 g of indolecarbonitrile 5 are dissolved in methanol under a        protective-gas atmosphere (N₂), palladium on active carbon        (Pd/C) is added, and the mixture is hydrogenated at room        temperature under atmospheric pressure with hydrogen until the        reaction is complete. For work-up, the reaction mixture is        filtered, and the filtrate is freed from solvent under reduced        pressure. The residue is taken up in methyl acetate and        extracted with water. The organic phase is separated off, dried        and evaporated. The residue is purified by chromatography on        silica gel using ethyl acetate as eluent, giving 4.2 g (84% of        theory) of a beige crystalline residue of compound 6.

1.6. Step f: Preparation of Compound 7

-   -   18.2 g of compound 6 are dissolved in 1000 ml of tetrahydrofuran        under a protective-gas atmosphere, and the solution is cooled to        0° C. A solution of 60 ml of Vitride in 60 ml of toluene is        subsequently added dropwise at such a rate that the temperature        remains in the range from 2 to 8° C., and the mixture is stirred        at 5° C. for a further three hours. During the addition of the        Vitride, a precipitate may form, which, however, generally        re-dissolves on subsequent stirring. Excess Vitride is        hydrolysed by addition of 250 ml of water, during which a        precipitate may form. A further 200 ml of water and 300 ml of        ethyl acetate are added, and the mixture is left to stand        overnight. The reaction mixture is subsequently filtered through        kieselguhr, the residue is discarded, and the filtrate phases        are separated. The organic phase is freed from solvent under        reduced pressure and purified by chromatography on silica gel        using ethyl acetate as eluent, giving 13.5 g (84% of theory) of        a beige crystalline residue of compound 7.

1.7. Step g: Preparation of Compound 8

-   -   A solution of 6 g of compound 7 in 80 ml of dichloromethane and        80 ml of tetrahydrofuran is cooled to 2° C. 2.3 ml of        methanesulfonyl chloride are added, the mixture is stirred        briefly, and 5.3 ml of triethylamine are subsequently added at        from 2 to 5° C. The mixture is subsequently stirred at 2° C. for        a further 2 hours. The reaction mixture is then poured into        ice-water, the aqueous phase is extracted, and the combined        organic phases are freed from solvent under reduced pressure,        giving 7.6 g (91% of theory) of a brown crystalline residue of        compound 8.

1.8. Step h: Preparation of Compound 10

-   -   0.40 gram of 4-(4-fluorobenzyl)piperidine (9) and 0.42 gram of        sodium hydrogencarbonate are added to a suspension of 0.50 gram        of compound 8 in 10 ml of acetonitrile with stirring, and the        mixture is stirred at 100° C. for 24 hours. The reaction mixture        is subsequently cooled to room temperature, and the solvent is        removed under reduced pressure. The residue obtained is purified        by chromatography on silica gel and dissolved in acetone, and        ethereal hydrochloric acid is added. The crystalline precipitate        which forms is separated off by filtration and dried, giving 230        mg (35% of theory) of compound 10        (4-{3-[4-(4-fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile        as the hydrochloride.

The following formula scheme relates to the preparation of4-{3-[4-(4-fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile inaccordance with Example 1. The lower-case letters a to h on the reactionarrows correspond to reaction steps a to h described above.

EXAMPLE 2 Process Steps a′ to g′: Preparation of Compound 18

Compound 18 was obtained analogously to the reaction sequence carriedout in Example 1 in reaction steps a to g in accordance with thefollowing formula scheme in reaction steps a′ to h′

5-{4-[3-(3-Cyano-1H-indol-5-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide20 can be obtained analogously to process step h of Example 1 inaccordance with the following conditions by reaction of compound 18 withcompound 19:

Step h′: Preparation of Compound 20

0.90 g of 5-piperazin-1-ylbenzofuran-2-carboxamide (19) and 1.4 g ofethyldiisopropylamine (DIPEA) are added with stirring to a suspension of1.00 gram of compound 18 in 30 ml of acetonitrile, and the mixture isrefluxed for 18 hours. The reaction mixture is subsequently cooled toroom temperature, methanol (20 ml) is added, and the mixture is refluxedfor a further three hours. The solvent is subsequently removed underreduced pressure, and the residue is purified by chromatography onsilica gel. The residue obtained is dissolved in acetone, and etherealhydrochloric acid is added. The crystalline precipitate which forms isseparated off by filtration and dried, giving 0.4 g (22% of theory) ofthe compound5-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide20 as the hydrochloride.

EXAMPLE 3

The following compounds can be obtained analogously to the processdescribed in Example 1 or Example 2:

-   5-{3-[4-(4-Cyanophenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (21);-   5-{4-[3-(3-Cyano-1H-indol-6-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide    (22);-   5-{3-[4-(2-Oxo-2H-chromen-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (23);-   5-{4-[3-(3-Cyano-1H-indol-4-yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide    (24);-   5-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-1-methanesulfonyl-1H-indole-3-carbonitrile    (25);-   5-[3-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-1H-indole-3-carbonitrile    (26);-   5-[3-(4-Benzo[1,2,    5]thiadiazol-4-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile    (27);-   3-{1-[3-(3-Cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carboxamide    (28);-   5-[3-(4-Quinolin-8-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile-   5-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (30);-   1-Methanesulfonyl-5-[3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-1H-indole-3-carbonitrile    (31),-   5-{3-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (32);-   5-{3-[4-(1H-Indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile    (33);-   5-{3-[4-(5-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile    (34);-   3-{1-[3-(3-Cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carbonitrile    (35);-   5-{3-[4-(6-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile    (36);-   5-{3-[4-(4-Fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile    (37);-   5-[3-(4-Benzo[d]isothiazol-3-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile    (38);-   4-{1-[3-(3-Cyano-1H-indol-6-yl)propyl]piperidin-4-yloxy}-benzamide-   (39);-   6-{3-[4-(2-Cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (40);-   6-{3-[4-(4-Cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (41);-   6-{3-[4-(4-Cyano-2-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile    (42);-   4-[3-(4-Pyrazol-1-ylmethyl-1-piperidyl)propyl]-1H-indole-3-carbonitrile    (43);-   6-{3-[4-(4-Fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (44);-   6-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (45);-   6-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    46);-   4-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (47);-   4-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (48);-   5-{3-[4-(4-Fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (49);-   5-{3-[4-(4-Fluorobenzyl)-1-piperidyil]propyl}-1H-indole-3-carbonitrile    (50);-   5-{3-[4-(2,4-Difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile    (51).

The compounds can be purified and/or characterised by HPLCchromatography. The characterisation of the compounds via the retentiontime (R_(t)) can be carried out on a 3μ Silica-Rod column with a 210second gradient from 20 to 100% water/acetonitrile/0.01% trifluoroaceticacid at a flow rate of 2.2 ml/minute and detection at a wavelength of220 nanometres.

Physical constants and analytical data (mass spectrometric data(HPLC-MS)) of compounds 20-43 synthesised as above are shown in Table I.

TABLE I Com- MW [M + H] R_(t)(HPLC)/ pound Structure g/mol HPLC-MS min20

429 21

370 22

429 23

413 24

429 25

463 26

415 27

404 28

426 29

397 30

403 31

493 32

384 33

384 34

401 35

409 36

401 37

401 38

403 39

403 40

400 41

400 42

400 43

348

Physical constants and analytical data (mass spectrometric data (FAB-MS)and retention times (HPLC)) of compounds 10 and 44-51 synthesised asabove are shown in Table II.

TABLE II Com- MW [M + H] R_(t)(HPLC)/ pound Structure g/mol HPLC-MS min10

375.49 376.20 1.428 44

375.49 376 1.203 45

393.48 394 1.236 46

377.47 378 1.172 47

393.48 394 1.443 48

377.47 378 1.347 49

394 50

376 51

378

The examples below relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of the active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of the active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of the active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of the active ingredient of the formula I are mixed with 99.5 gof Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

EXAMPLE I Inhalation Spray

14 g of active ingredient of the formula I are dissolved in 10 l ofisotonic NaCl solution, and the solution is transferred intocommercially available spray containers with a pump mechanism. Thesolution can be sprayed into the mouth or nose. One spray shot (about0.1 ml) corresponds to a dose of about 0.14 mg.

1-9. (canceled)
 10. A method for inhibiting the activity of a glycinetransporter comprising contacting said transporter with a compound ofFormula I

wherein R¹ is H, A or SO₂A, A is straight-chain or branched alkyl havingfrom 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms oralkoxyalkyl having from 2 to 10-carbon atoms, and D-E is R²C═CR⁴ orR²R³C—CR⁴R⁵, in which R², R³, R⁴ and R⁵ are selected, independently,from H, A, cycloalkyl having from 3 to 7 carbon atoms, Hal, CH₂Hal,CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)N(R⁶)₂, (CH₂)_(n)N(R⁶)Ar,(CH₂)_(n)N(R⁶)Het, (CH₂)_(n)N(Ar)₂, (CH₂)_(n)N(Het)₂, (CH₂)_(n)COOR⁶,(CH₂)_(n)COOAr, (CH₂)_(n)COOHet, (CH₂)_(n)CON(R⁶)₂, (CH₂)_(n)CON(R⁶)Ar,(CH₂)_(n)CON(R⁶)Het, (CH₂)_(n)CON(Ar)₂, (CH₂)_(n)CON(Het)₂,(CH₂)_(n)NR⁶COR⁶, (CH₂)_(n)NR⁶CON(R⁶)₂, (CH₂)_(n)NR⁶SO₂A,(CH₂)_(n)SO₂N(R⁶)₂, (CH₂)_(n)SO₂NR⁶(CH₂)_(m)Ar,(CH₂)_(n)SO₂NR⁶(CH₂)_(m)Het, (CH₂)_(n)S(O)_(w)R⁶, (CH₂)_(n)S(O)_(w)Ar,(CH₂)_(n)S(O)_(w)Het, (CH₂)_(n)OOCR⁶, (CH₂)_(n)Het, (CH₂)_(n)Ar,(CH₂)_(n)COR⁶, (CH₂)_(n)CO(CH₂)_(m)Ar, (CH₂)_(n)CO(CH₂)_(m)Het,(CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het, (CH₂)OR⁶,(CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het, (CH₂)_(n)SR⁶,(CH₂)_(n)S(CH₂)_(m)Ar, (CH₂)_(n)S(CH₂)_(m)Het, (CH₂)_(n)N(R⁶(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het, (CH₂CON(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Ar, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Het, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA,(CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR⁶, (CH₂)_(n)OC(O)N(R⁶)₂,(CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het,(CH₂)_(n)NR⁶COOR⁶, (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar,(CH₂)_(n)NR⁶COO(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)CH₂CH₂OR⁶,(CH₂)_(n)N(R⁶)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁶)C(R⁶)HCOOR⁶,(CH₂)_(n)N(R⁶)CH₂COHet, (CH₂)_(n)N(R⁶)CH_(n)Het,(CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)CH₂COOR⁶, (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)₂,CH═CHCOOR⁶, CH═CHCH₂NR⁶Het, CH═CHCH₂N(R⁶)₂, CH═CHCH₂OR⁶,(CH₂)_(n)(COOR⁶)COOR⁶, (CH₂)_(n)N(CONH₂)COOR⁶, (CH₂)_(n)N(CONH₂)CONH₂,(CH₂)_(n)N(CH₂COOR⁶)COOR⁶, (CH₂)_(n)N(CH₂CONH₂)COOR⁶,(CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR⁶COR⁶, (CH₂)_(n)CHR⁶COOR⁶,(CH₂)_(n)CHR⁶CH₂OR⁶, (CH₂)_(n)OCN or (CH₂)_(n)NCO, in which R⁶ isselected independently, from H, A or cycloalkyl having from 3 to 7carbon atoms, Het is a saturated, unsaturated or aromatic mono- orbicyclic heterocyclic radical which is unsubstituted or mono- orpolysubstituted by A, Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂,NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶,Ar is an aromatic hydrocarbon radical having from 6 to 14 carbon atomswhich is unsubstituted or mono- or polysubstituted by A, Hal, NO₂, CN,OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶,SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶, w is 0, 1, 2 or 3, and n and m,independently of one another, are 0, 1, 2, 3, 4 or 5: X¹ is (CHR⁷)_(g)or (CHR⁷)_(h)—O—(CHR^(g))_(k), in which O is selected from O, S, N—R⁶,(O—CHR⁷)_(g), (CHR⁷—O)_(g), CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g),(CHR⁹CHR¹⁰—O)_(g), C═O, C═S, C═NR⁶, CH(OR⁶), C(OR⁶)(OR⁶), C(═O)O,OC(═O), OC(═O)O, C(═O)N(R⁶), N(R⁶)C(═O), C(═S)N(R⁶), N(R⁶)C(═S),OC(═O)N(R⁶), N(R⁶)C(═O)O, CH═N—O, CH═N—NR⁶, OC(O)NR⁶, NR⁶C(O)O, S═O,SO₂, SO₂NR⁶ and NR⁶SO₂, g is 1, 2, 3, 4, 5 or 6, h and k, independentlyof one another, are 0, 1, 2, 3,4, 5 or 6, and R⁷, R⁸, R⁹, R¹⁰ and R¹²,independently of one another. are as defined for R² to R⁵; p is 0, 1, 2or 3, E is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar or cycloalkyl having from 3to 7 carbon atoms, G is an optionally substituted alkylene radicalhaving from 1 to 4 carbon atoms, where the substituents are selectedfrom the meanings indicated for R⁴, or E and G, together with the N atomto which they are bonded, are an un-substituted or substituted 5-, 6- or7-membered, mono- or bicyclic heterocyclic radical, which may have 1, 2or 3 further heteroatoms selected from N, O and S, X² is a bond or isselected, independently, from the meanings indicated for X¹, Z is H oris a saturated, mono- or polyethylenically unsaturated or aromaticcarbocyclic radical having from 5 to 10 carbon atoms or a saturated,mono- or polyethylenically unsaturated or aromatic heterocyclic radicalhaving from 4 to 9 carbon atoms, where the carbocyclic or heterocyclicradical may be mono- or polysubstituted, where the substituents ateselected, independently of one another, from the meanings of R² to R⁵other than H, and where the heterocyclic radical contains from 1 to 4heteroatoms selected, independently if one another, from N, O and S, andHal is F, Cl, Br or I, or a pharmaceutically acceptable salt. solvate,stereoisomer or mixture of said compound of Formula I.
 11. (canceled)12. A method for preventing or treating a 5HT-mediated diseasecomprising administering to a subject in need thereof a compound ofFormula I

wherein R¹ is H, A or SO₂A, A is straight-chain or branched alkyl havingfrom 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms oralkoxyalkyl having from 2 to 10 carbon atoms, and D-E is R²C═CR⁴ orR²R³C—CR⁴R⁵, in which R², R³, R⁴ and R⁵ are selected, independently,from H, A, cycloalkyl having from 3 to 7 carbon atoms, Hal, CH₂Hal,CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)N(R⁶)₂, (CH₂)_(n)N(R⁶)Ar,(CH₂)_(n)N(R⁶)Het, (CH₂)_(n)N(Ar)₂, (CH₂)_(n)N(Het)₂, (CH₂)_(n)COOR⁶,(CH₂)_(n)COOAr, (CH₂)_(n)COOHet, (CH₂)_(n)CON(R⁶)₂, (CH₂)_(n)CON(R⁶)Ar,(CH₂)_(n)CON(R⁶)Het, (CH₂)_(n)CON(Ar)₂, (CH₂)_(n)CON(Het)₂,(CH₂)_(n)NR⁶COR⁶, (CH₂)_(n)NR⁶CON(R⁶)₂, (CH₂)_(n)NR⁶SO₂A,(CH₂)_(n)SO₂N(R⁶)₂, (CH₂)_(n)SO₂NR⁶(CH₂)_(m)Ar,(CH₂)_(n)SO₂NR⁶(CH₂)_(m)Het, (CH₂)_(n)S(O)_(w)R⁶, (CH₂)_(n)S(O)_(w)Ar,(CH₂)_(n)S(O)_(w)Het, (CH₂)_(n)OOCR⁶, (CH₂)_(n)Het, (CH₂)_(n)Ar,(CH₂)_(n)COR⁶, (CH₂)_(n)CO(CH₂)_(m)Ar, (CH₂)_(n)CO(CH₂)_(m)Het,(CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het, (CH₂)OR⁶,(CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het, (CH₂)_(n)SR⁶,(CH₂)_(n)S(CH₂)_(m)Ar, (CH₂)_(n)S(CH₂)_(m)Het, (CH₂)_(n)N(R⁶(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het, (CH₂CON(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Ar, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Het, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA,(CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR⁶, (CH₂)_(n)OC(O)N(R⁶)₂,(CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het,(CH₂)_(n)NR⁶COOR⁶, (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar,(CH₂)_(n)NR⁶COO(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)CH₂CH₂OR⁶,(CH₂)_(n)N(R⁶)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁶)C(R⁶)HCOOR⁶,(CH₂)_(n)N(R⁶)CH₂COHet, (CH₂)_(n)N(R⁶)CH_(n)Het,(CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)CH₂COOR⁶, (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)₂,CH═CHCOOR⁶, CH═CHCH₂NR⁶Het, CH═CHCH₂N(R⁶)₂, CH═CHCH₂OR⁶,(CH₂)_(n)(COOR⁶)COOR⁶, (CH₂)_(n)N(CONH₂)COOR⁶, (CH₂)_(n)N(CONH₂)CONH₂,(CH₂)_(n)N(CH₂COOR⁶)COOR⁶, (CH₂)_(n)N(CH₂CONH₂)COOR⁶,(CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR⁶COR⁶, (CH₂)_(n)CHR⁶COOR⁶,(CH₂)_(n)CHR⁶CH₂OR⁶, (CH₂)_(n)OCN or (CH₂)_(n)NCO, in which R⁶ isselected, independently, from H, A or cycloalkyl having from 3 to 7carbon atoms, Het is a saturated, unsaturated or aromatic mono- orbicyclic heterocyclic radical which is unsubstituted or mono- orpolysubstituted by A, Hal. NO₂,CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂,NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶,Ar is an aromatic hydrocarbon radical having from 6 to 14 carbon atomswhich is unsubstituted or mono- or polysubstituted by A, Hal, NO₂, CN,OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶,SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶, w is 0, 1, 2 or 3, and n and m,independently of one another, are 0, 1, 2, 3, 4 or 5; X¹ is (CHR⁷)_(g)or (CHR⁷)_(h)-Q-(CHR⁸)_(k), in which Q is selected from O, S, N—R⁶,(O—CHR⁷)_(g), (CHR⁷—O)_(g), CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g),(CHR⁹CHR¹⁰—O)_(g), C═O, C═S, C═NR⁶, CH(OR⁶), C(OR⁶)(OR⁶), C(═O)O,OC(═O), OC(═O)O, C(═O)N(R⁶), N(R⁶)C(═O), C(═S)N(R⁶), N(R⁶)C(═S),OC(═O)N(R⁶), N(R⁶)C(═O)O, CH═N—O, CH═N—NR⁶, OC(O)NR⁶, NR⁶C(O)O, S═O,SO₂, SO₂NR⁶ and NR⁶SO₂, g is 1, 2, 3, 4, 5 or 6, h and k, independentlyof one another. are 0, 1, 2, 3, 4, 5 or 6, and R⁷, R⁸, R⁹, R¹⁰ and R¹²,independently of one another, are as defined for R² to R⁵; p is 0, 1, 2or 3, E is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar or cycloalkyl having from 3to 7 carbon atoms, G is an optionally substituted alkylene radicalhaving from 1 to 4 carbon atoms, where the substituents are selectedfrom the meanings indicated for R⁴; or E and G, together with the N atomto which they are bonded, are an unsubstituted or substituted 5-, 6- or7-membered, mono- or bicyclic heterocyclic radical, which may have 1, 2or 3 further heteroatoms selected from N, O and S, X² is a bond or isselected, independently, from the meanings indicated for X¹, Z is H oris a saturated, mono- or polyethylenically unsaturated or aromaticcarbocyclic radical having from 5 to 10 carbon atoms or a saturated,mono- or polyethylenically unsaturated or aromatic heterocyclic radicalhaving from 4 to 9 carbon atoms, where the carbocyclic or, heterocyclicradical may be mono- or polysubstituted, where the substituents areselected. independently of one another, from the meanings of R² to R⁵other than H, and where the heterocyclic radical contains from 1 to 4heteroatoms selected, independently of one another, from N, O and S, andHal is F, Cl, Br or I, or a pharmaceutically acceptable salt, solvate,stereoisomer or mixture of said compound of Formula I.
 13. A methodaccording to claim 12, wherein said disease is depression, strokes,cerebral ischaemia, extrapyramidal motor side effects of neuroleptics orof Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis, brain or spinal cord trauma, obsessive-compulsive disorder,sleeping disorders, tardive dyskinesia, learning disorders, age-relatedmemory disorders, eating disorders or sexual dysfunction.
 14. A methodfor treating or preventing schizophrenia, depression, dementia,Parkinson's disease, Alzheimer's disease, Lewy bodies dementia,Huntington's disease, Tourette's syndrome, anxiety, learning and memoryimpairments, neurodegenerative diseases, cognitive impairments, nicotinedependence or pain, comprising administering to a subject in needthereof a compound of Formula I

wherein R¹ is H, A or SO₂A, A is straight-chain or branched alkyl havingfrom 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms oralkoxyalkyl having from 2 to 10 carbon atoms, and D-E is R²C═CR⁴orR²R³C—CR⁴R⁵, in which R², R³, R⁴ and R⁵ are selected, independently,from H, A, cycloalkyl having from 3 to 7 carbon atoms, Hal, CH₂Hal,CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)N(R⁶)₂, (CH₂)_(n)N(R⁶)Ar,(CH₂)_(n)N(R⁶)Het, (CH₂)_(n)N(Ar)₂, (CH₂)_(n)N(Het)₂, (CH₂)_(n)COOR⁶,(CH₂)_(n)COOAr, (CH₂)_(n)COOHet, (CH₂)_(n)CON(R⁶)₂, (CH₂)_(n)CON(R⁶)Ar,(CH₂)_(n)CON(R⁶)Het, (CH₂)_(n)CON(Ar)₂, (CH₂)_(n)CON(Het)₂,(CH₂)_(n)NR⁶COR⁶, (CH₂)_(n)NR⁶CON(R⁶)₂, (CH₂)_(n)NR⁶SO₂A,(CH₂)_(n)SO₂N(R⁶)₂, (CH₂)_(n)SO₂NR⁶(CH₂)_(m)Ar,(CH₂)_(n)SO₂NR⁶(CH₂)_(m)Het, (CH₂)_(n)S(O)_(w)R⁶, (CH₂)_(n)S(O)_(w)Ar,(CH₂)_(n)S(O)_(w)Het, (CH₂)_(n)OOCR⁶, (CH₂)_(n)Het, (CH₂)_(n)Ar,(CH₂)_(n)COR⁶, (CH₂)_(n)CO(CH₂)_(m)Ar, (CH₂)_(n)CO(CH₂)_(m)Het,(CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het, (CH₂)OR⁶,(CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het, (CH₂)_(n)SR⁶,(CH₂)_(n)S(CH₂)_(m)Ar, (CH₂)_(n)S(CH₂)_(m)Het, (CH₂)_(n)N(R⁶(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar, (CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het, (CH₂CON(R⁶)(CH₂)_(m)Ar,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Ar, (CH₂)_(n)CON(R⁶)(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)CO(CH₂)_(m)Het, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA,(CH₂)_(n)CH═N-Het, (CH₂)_(n)OCOR⁶, (CH₂)_(n)OC(O)N(R⁶)₂,(CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Het,(CH₂)_(n)NR⁶COOR⁶, (CH₂)_(n)NR⁶COO(CH₂)_(m)Ar,(CH₂)_(n)NR⁶COO(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)CH₂CH₂OR⁶,(CH₂)_(n)N(R⁶)CH₂CH₂OCF₃, (CH₂)_(n)N(R⁶)C(R⁶)HCOOR⁶,(CH₂)_(n)N(R⁶)CH₂COHet, (CH₂)_(n)N(R⁶)CH_(n)Het,(CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)CH₂COOR⁶, (CH₂)_(n)N(R⁶)CH₂CH₂N(R⁶)₂,CH═CHCOOR⁶, CH═CHCH₂NR⁶Het, CH═CHCH₂N(R⁶)₂, CH═CHCH₂OR⁶,(CH₂)_(n)(COOR⁶)COOR⁶, (CH₂)_(n)N(CONH₂)COOR⁶, (CH₂)_(n)N(CONH₂)CONH₂,(CH₂)_(n)N(CH₂COOR⁶)COOR⁶, (CH₂)_(n)N(CH₂CONH₂)COOR⁶,(CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR⁶COR⁶, (CH₂)_(n)CHR⁶COOR⁶,(CH₂)_(n)CHR⁶CH₂OR⁶, (CH₂)_(n)OCN or (CH₂)_(n)NCO, in which R⁶ isselected, independently from H, A or cycloalkyl having from 3 to 7carbon atoms, Het is a saturated, unsaturated or aromatic mono- orbicyclic heterocyclic radical which is unsubstituted or mono- orpolysubstituted by A, Hal, NO₂, CN, OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂,NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶,Ar is an aromatic hydrocarbon radical having from 6 to 14 carbon atomswhich is unsubstituted ort mono- or polysubstituted by A, Hal, NO₂, CN,OR⁶, N(R⁶)₂, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶,SO₂N(R⁶)₂, S(O)_(w)A and/or OOCR⁶, w is 0, 1, 2 or 3, and n and m,independently of one another. are 0, 1, 2, 3, 4 or 5; X¹ is (CHR⁷)_(g)or (CHR⁷)_(h)—O—(CHR⁸)_(k), in which O is selected from O, S, N—R⁶,(O—CHR⁷)_(g), (CHR⁷—O)_(g), CR⁹═CR¹⁰, (O—CHR⁹CHR¹⁰)_(g),(CHR⁹CHR¹⁰—O)_(g), C═O, C═S, C═NR⁶, CH(OR⁶), C(OR⁶)(OR⁶), C(═O)O,OC(═O), OC(═O)O, C(═O)N(R⁶), N(R⁶)C(═O), C(═S)N(R⁶), N(R⁶)C(═S),OC(═O)N(R⁶), N(R⁶)C(═O)O, CH═N—O, CH═N—NR⁶, OC(O)NR⁶, NR⁶C(O)O, S═O,SO₂, SO₂NR⁶, and NR⁶SO₂, g is 1, 2, 3, 4, 5 or 6, h and k, independentlyof one another. are 0, 1, 2, 3, 4, 5 or 6, and R⁷, R⁸, R⁹, R¹⁰ and R¹²,independently of one another, are as defined for R² to R⁵; p is 0, 1, 2or 3, E is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar or cycloalkyl having from 3to 7 carbon atoms, G is an optionally substituted alkylene radicalhaving, from 1 to 4 carbon atoms, where the substituents are selectedfrom the meanings indicated for R⁴, or E and G, together with the N atomto which they are bonded, are an unsubstituted or substituted 5-, 6- or7-membered, mono- or bicyclic heterocyclic radical, which may have 1, 2or 3 further heteroatoms selected from N, O and S, X² is a bond or isselected. independently, from the meanings indicated for X¹, Z is H oris a saturated mono- or polyethylenically unsaturated or aromaticcarbocyclic radical having from 5 to 10 carbon atoms or a saturated,mono- or polyethylenically unsaturated or aromatic heterocyclic radicalhaving from 4 to 9 carbon atoms, where the carbocyclic or heterocyclicradical may be mono- or polysubstituted, where the substituents areselected. independently of one another, from the meanings of R² to R⁵other than H, and where the heterocyclic radical contains from 1 to 4heteroatoms selected, independently of one another, from N, O and S, andHal is F, Cl, Br or I, or a pharmaceutically acceptable salt, solvate,stereoisomer or mixture of said compound of Formula I. 15.-19.(canceled)
 20. The method according to claim 12, comprisingadministering to said subject a compound of formula Ia

wherein R¹ is H, A or SO₂A A is straight-chain or branched alkyl havingfrom 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms oralkoxyalkyl having from 2 to 10 carbon atoms, and D-E R²C═CR⁴, whereinR² is H or methyl and R⁴ is CN X¹ is (CHR⁷)_(g) g is 1, 2, 3, 4, 5 or 6,R⁷ is, independently, has the meanings indicated for R² to R⁵; Y is CHor N, q is 0, p and r are each, independently of one another, 0, 1, 2 or3 Hal is F, Cl, Br ox I, R¹² and R¹³, are each, independently of oneanother, R⁴ or are, independently of one another, Hal, CN, NO₂, OR⁶,N(R⁶)₂, NO₂, CN, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶,SO₂NR⁶, S(O)_(w)A, OOCR⁶ or C(NH)NOH, and X²-Z is at least one of

wherein X² is a bond, R¹⁴ is, independently, Hal, A, (CH₂)_(n)Het,(CH₂)_(n)Ar, (CH₂)_(n)COO(CH₂)_(m)Ar, (CH₂)_(n)COO(CH₂)_(m)Het,(CH₂)_(n)OR⁶, (CH₂)_(n)O(CH₂)_(m)Ar, (CH₂)_(n)O(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)(CH₂)_(m)Het,(CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Ar, (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Ar,(CH₂)_(n)SO₂N(R⁶)(CH₂)_(m)Het, (CH₂)_(n)N(R⁶)SO₂(CH₂)_(m)Het,(CH₂)_(n)N(R⁶)₂, (CH₂)_(n)NHOA, (CH₂)_(n)(R⁶)Het, (CH₂)_(n)OCOR⁶,(CH₂)_(n)OC(O)N(R⁶)₂, (CH₂)_(n)OC(O)NR⁶(CH₂)_(m)Ar,(CH₂)_(n)OC(O)NR⁶(CH₂)_(m),Het, (CH₂)_(n)NR⁶COOR⁶,(CH₂)_(n)NR⁶COO(CH₂)_(m)Ar, (CH₂)_(n)NR⁶COO(CH₂)_(m)Het, or CN w is 0,1, 2 or 3, t is 0, 1, 2, 3, 4 or 5, and m is 0, 1, 2, 3, 4, or 5 n is 0,1, 2, or 3 R′ is H, A, (CH₂)_(n)Het, (CH₂)_(n)Ar, cycloalkyl having from3 to 7 carbon atoms or SO₂A; or a pharmaceutically salt, solvate,stereoisomer, or mixture thereof.
 21. The method according to claim 20,comprising administering to said subject a compound of formula Ia acompound of formula IIa

wherein R¹ and R² are as defined in claim 20; and Y-Z is a radical whichcomprises at least one of

or a radical which comprises at least one of

or a pharmaceutically salt, solvate, stereoisomer, or mixture thereof.22. The method according to claim 20, comprising administering to saidsubject a compound of formula Ia

wherein R¹ is H or A A is straight-chain or branched allyl having from 1to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms oralkoxyalkyl having from 2 to 10 carbon atoms, and D-E R²C═CR⁴, whereinR² is H or methyl and R⁴ is CN X¹ is (CHR⁷)_(g) g is 3, R⁷,independently, has the meanings indicated for R² to R⁵; Y is CH or N, qis 0, p and t are, independently of one another, 0, 1, 2 or 3 Hal is F,Cl, Bfr or I, R¹² and R¹³, are, independently of one another, Hal, CN,NO₂, OR⁶, N(R⁶)₂, NO₂, CN, COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂,NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)_(w)A, OOCR⁶ or C(NH)N OH, and X²-Z is atleast one of

wherein X² is a bond, R¹⁴ is, independently, Hal, NO₂, OR⁶, N(R⁶)₂, CN,COOR⁶, CON(R⁶)₂, NR⁶COR⁶, NR⁶CON(R⁶)₂, NR⁶SO₂A, COR⁶, SO₂NR⁶, S(O)_(w)A,OOCR⁶ and/or C(NH)NOH, w is 0,1, 2 or 3, t is 1, 2,3, and R′ is H, A,(CH₂)_(n)Het, (CH₂)_(n)Ar, cycloalkyl having from 3 to 7 carbon atoms orSO₂A; or a pharmaceutically salt, solvate, stereoisomer, or mixturethereof.
 23. The method according to claim 12, comprising administeringto said subject a compound which is a)6-{3-[4-(4-fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;b)6-{3-[4-(2,4-difluorobenzyl)-1-piperidyl]propyl}-H-indole-3-carbonitrile;c)6-{3-[4-(4-fluorophenoxy)-1-piperidyl]propyl}1H-indole-3-carbonitrile;d)4-{3-[4-(4-fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;e)4-{3-[4-(2,4-difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;f) 4{3-[4-(4-fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile; g)5-{3-[4-(4-fluorophenoxy)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;h)5-{3-[4-(4-fluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;i)5-{3-[4-(2,4-difluorobenzyl)-1-piperidyl]propyl}-1H-indole-3-carbonitrile;j)5-{3-[4-(4-cyanophenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;k)5-{4-[3-(3-cyano-1H-indol-6yl)propyl]piperazin-1-yl}benzofuran-2-carboxamide;l)5-{3-[4-(2-oxo-2H-chromen-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;m)5-{4-[3-(3-cyano-1H-indol-4-yl)propyl]piperazin-1-yl}-benzofuran-2-carboxamide;n)5-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-benzofuran-2-carboxamide;o)5-{3-[4-(1H-indol-4-yl)-piperazin-1-yl]propyl}-1-methanesulfonyl-1H-indole-3-carbonitrile;p)5-[3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-1H-indole-3-carbonitrile;q)5-[3-(4-benzo[1,2,5]thiadiazol-4-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile;r)3-{1-[3-(3-cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carboxamide;s) 5-[3-(4-quinolin-8-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile;t)5-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-41H-indole-3-carbonitrile;u)1-methanesulfonyl-5-[3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)propyl]-4H-indole-3-carbonitrile;v)5-(3-[4-(1H-indol-4-yl)piperazin-1-yl]propyl)-1H-indole-3-carbonitrile;w)5-{3-[4-(H-indol-3-yl)piperidin-1-yl]propyl}-4H-indole-3-carbonitrile;x)5-{3-[4-(5-fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile;y)3-{1-[3-(3-cyano-1H-indol-5-yl)propyl]piperidin-4-yl}-1H-indole-5-carbonitrile;z)5-{3-[4-(6-fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile;aa)5-{3-[4-(4-fluoro-1H-indol-3-yl)piperidin-1-yl]propyl}-1H-indole-3-carbonitrile;bb)5-[3-(4-benzo[d]isothiazol-3-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile;cc) 4-{1-[3-(3-cyano-1H-indol-6-yl)propyl]piperidin-4-yloxy}benzamide;dd)6-{3-[4-(2-cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;ee)6-{3-[4-(4-cyano-3-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;ff)6-{3-[4-(4-cyano-2-methoxyphenyl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;gg)4-[3-(4-pyrazol-1-ylmethyl-1-piperidyl)propyl]-1H-indole-3-carbonitrile;hh)N-(6-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)acetamide;ii) 5-{3-[(pyridin-3-ylmethyl)amino]propyl}-1H-indole-3-carbonitrile;jj)5-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;kk)5-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]-1H-indole-3-carbonitrile;ll)5-{3-[(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]propyl}-1H-indole-3-carbonitrile;mm)5-{3-[4-(3-methoxyphenyl)-3-methylpiperazin-4-yl]propyl}-1H-indole-3-carbonitrile;nn)5-{3-[4-(1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)piperazin-1-yl]propyl}1H-indole-3-carbonitrile;oo)N-(4-{1-[3-(3-cyano-1H-indol-5-yl)propyl]piperidin-4-ylmethyl}-phenyl)acetamide;pp)5-{3-[4-(4-pyridin-3-ylthiazol-2-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;qq) ethyl2-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-thiazole-4-carboxylate;rr)5-{3-[3-(2-oxopyrrolidin-1-yl)propylamino]propyl}-1H-indole-3-carbonitrile;ss) ethyl(6-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)carbamate;tt)5-{3-[4-(3-amino-2-oxo-2H-chromen-6-yl)piperazin-1-yl]propyl}-1H-indole-3-carbonitrile;uu)methyl(6-{4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazin-1-yl}-2-oxo-2H-chromen-3-yl)carbamate;vv)2-{4-[3-(3-cyano-1H-indol-5-yl)propyl]-piperazin-1-yl}thiazole-4-carboxamide;or ww) 4-[3-(3-cyano-1H-indol-5-yl)propyl]piperazine-1-thiocarboxamide;or a pharmaceutically acceptable salt, solvate, stereoisomer or mixturethereof.